Sulphonylpyrrole Hydrochloride Salts as Histone Deacetylases Inhibitors

ABSTRACT

Compounds of a certain formula 1, 
     
       
         
         
             
             
         
       
     
     in which R1, R2, R3, R4, R5, R6 and R7 have the meanings indicated in the description, as well as salts thereof are novel effective HDAC inhibitors.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel N-sulphonylpyrrole derivatives, which areused in the pharmaceutical industry for the production of pharmaceuticalcompositions.

The invention further relates to certain crystalline salts of theseN-sulphonylpyrrole derivatives, which are used in the pharmaceuticalindustry for the production of pharmaceutical compositions.

KNOWN TECHNICAL BACKGROUND

Transcriptional regulation in cells is a complex biological process. Onebasic principle is regulation by posttranslational modification ofhistone proteins, namely histone proteins H2A/B, H3 and H4 forming theoctameric histone core complex. These complex N-terminal modificationsat lysine residues by acetylation or methylation and at serine residuesby phosphorylation constitute part of the so called “histone code”(Strahl & Ellis, Nature 403, 41-45, 2000). In a simple model,acetylation of positively charged lysine residues decreases affinity tonegatively charged DNA, which now becomes accessible for the entry oftranscription factors.

Histone acetylation and deacetylation is catalysed by histoneacetyltransferases (HATs) and histone deacetylases (HDACs). HDACs areassociated with transcriptional repressor complexes, switching chromatinto a transcriptionally inactive, silent structure (Marks et al. NatureCancer Rev 1, 194-202, 2001). The opposite holds true for HATs which areassociated with transcriptional activator complexes. Three differentclasses of HDACs have been described so far, namely class I (HDAC 1-3,8) with Mr=42-55 kDa primarily located in the nucleus and sensitivetowards inhibition by Trichostatin A (TSA), class II (HDAC 4-7, 9, 10)with Mr=120-130 kDa and TSA sensitivity and class 111 (Sir2 homologues)which are quite distinct by their NAD⁺ dependency and TSA insensitivity(Ruijter et al. Biochem. J. 370, 737-749, 2003; Khochbin et al. CurrOpin Gen Dev 11, 162-166, 2001; Verdin et al. Trends Gen 19, 286-293,2003). HDAC 11 with Mr=39 kDa was cloned recently and displayed homologyto class I and II family members (Gao et al. J Biol Chem277,25748-25755, 2002). HATs and HDACs exist in large complexes togetherwith transcription factor and platform proteins in cells (Fischle et al.Mol Cell 9, 45-47, 2002). Surprisingly, only about 2% of all genes areregulated by histone acetylation (von Lint et al. Gene Expression 5,245-253, 1996). New studies with SAHA in multiple myeloma cells showedthat these transcriptional changes can be grouped into distinctfunctional gene classes important for eg regulation of apoptosis orproliferation (Mitsiades et al. Proc Natl Acad Sci 101, pp 540, 2004).Substrates different to histone proteins exist. For HDACs these includetranscription factors like p53 and TFII E/or chaperones like Hsp90(Johnstone & Licht, Cancer Cell 4, 13-18, 2003). Therefore the correctname for HDACs would be lysine-specific protein deacetylases. As aconsequence of these findings, inhibitors of HDACs effect not onlychromatin structure and gene transcription but also protein function andstability by regulating protein acetylation in general. This function ofHDACs in protein acetylation might also be important for understandingof immediate gene repression by treatment with HDIs (von Lint et al.Gene Expression 5, 245-253, 1996). In this regard, proteins involved inoncogenic transformation, apoptosis regulation and malignant cell growthare of particular importance.

Different publications highlight the importance of histone acetylationfor cancer development (reviewed by Kramer et al. Trends EndocrinMetabol 12, 294-300, 2001; Marks et al. Nature Cancer Rev 1, 194-202,2001). These diseases include

-   (i) mutations of the HAT cAMP response element binding protein (CBP)    associated with Rubinstein-Taybi syndrome, a cancer predisposition    (Murata et al. Hum Mol Genet. 10, 1071-1076, 2001),-   (ii) aberrant recruitment of HDAC1 activity by transcription factors    in acute promyelocytic leukemia (APL) by the PML-retinoic acid    receptor a fusion gene (He et al. Nat genet 18, 126-135, 1998)-   (iii) aberrant recruitment of HDAC activity by the overexpressed    BCL6 protein in non-Hodgkins lymphoma (Dhordain et al. Nucleic Acid    Res 26, 4645-4651, 1998) and finally-   (iv) aberrant recruitment of HDAC activity by the AML-ETO fusion    protein in acute myelogenous leukemia (AML M2 subtype; Wang et al.    Proc Natl Acad Sci USA 95, 10860-10865, 1998). In this AML subtype,    the recruitment of HDAC1 activity causally leads to gene silencing,    a differentiation block and oncogenic transformation.-   (v) HDAC1 gene knock-out in mice showed that HDAC1 has a profound    function in embryonal stem cell proliferation by repressing    cyclin-dependent kinase inhibitors p21^(waf1) and p27^(kip1) (Lagger    et al. Embo J. 21, 2672-2681, 2002). Since p21^(waf1) is induced by    HDIs in many cancer cell lines, HDAC1 might be a crucial component    in cancer cell proliferation as well. Initial siRNA based gene-knock    down experiments in HeLa cells support this hypothesis (Glaser et    al. 310, 529-536, 2003)-   (vi) HDAC2 is overexpressed in colon carcinoma upon constitutive    activation of the wnt/β-catenin/TCF signalling pathway by loss of    functional adenomatosis polyposis coli (APC) protein as reported by    Zhu et al. recently (Cancer Cell 5, 455-463, 2004)

On the molecular level, a plethora of published data with various HDACinhibitors like Trichostatin A (TSA) showed that many cancer relevantgenes are up- or down regulated. These include p21^(waf1), Cyclin E,transforming growth factor β (TGFβ), p53 or the von Hippel-Lindau (VHL)tumor suppressor genes, which are upregulated, whereas Bcl-XL, bcl2,hypoxia inducible factor (HIF)1α, vascular endothelial growth factor(VEGF) and cyclin A/D are down-regulated by HDAC inhibition (reviewed byKramer et al. Trends Endocrin Metabol 12, 294-300, 2001). HDACinhibitors arrest cells at G1 and G2/M within the cell cycle and depleteS-phase cells, as shown for Depsipeptide as an example (Sandor et al.,British J Cancer 83, 817-825, 2000). HDAC inhibitory compounds inducep53 and caspase3/8 independent apoptosis and have broad anti-tumoractivity. Anti-angiogenic activity was described also, which might berelated to down-regulation of VEGF and HIF1α. In summary, HDACinhibition effects tumor cells at different molecular levels andmultiple cellular proteins are targeted.

Interestingly, HDAC inhibitors were found to induce cellulardifferentiation and this pharmacological activity might contribute totheir anti-cancer activity as well. For example it was shown recentlythat suberoylanilide hydroxamic acid (SAHA) induces differentiation ofbreast cancer cell lines, exemplified by resynthesis of milk fatmembrane globule protein (MFMG), milk fat globule protein and lipid(Munster et al. Cancer Res. 61, 8492, 2001).

There is growing rational for synergism of HDAC inhibitors withchemotherapeutic as well as target specific cancer drugs. For example,synergism was shown for SAHA with the kinase/cdk inhibitor flavopiridol(Alemenara et al. Leukemia 16, 1331-1343, 2002), for LAQ-824 with thebcr-abl kinase inhibitor Glivec in CML cells (Nimmanapalli et al. CancerRes. 63, 5126-5135, 2003) and for SAHA and Trichostatin A (TSA) withetoposide (VP16), cisplatin and doxorubicin (Kim et al. Cancer Res. 63,7291-7300, 2003) and LBH589 with the hsp90 inhibitor17-allyl-amino-demethoxy-geldanamycin (17-MG; George et al. Bloodonline, Oct. 28, 2004). Also it was shown that HDAC inhibition causesreexpression of estrogen or androgen receptors in breast and prostatecancer cells with the potential to resensitize these tumors toanti-hormone therapy (Yang et al. Cancer Res. 60, 6890-6894, 2000;Nakayama et al. Lab Invest 80, 1789-1796, 2000).

HDAC inhibitors from various chemical classes were described in theliterature with four most important classes, namely (i) hydroxamic acidanalogs, (ii) benzamide analogs, (iii) cyclic peptides/peptolides and(iv) fatty acid analogs. A comprehensive summary of known HDACinhibitors was published recently (Miller et al. J Med Chem 46,5097-5116, 2003). There is only limited data published regardingspecificity of these histone deacetylase inhibitors. In general mosthydroxamate based HDI are not specific regarding class I and II HDACenzymes. For example. TSA inhibits HDACs 1, 3, 4, 6 and 10 with IC₅₀values around 20 nM, whereas HDAC8 was inhibited with IC₅₀=0.49 μM(Tatamiya et al, AACR Annual Meeting 2004, Abstract #2451). But thereare exceptions like the experimental HDI Tubacin, selective for theclass II enzyme HDAC 6 (Haggarty et al. Proc natl Acad Sci USA 100,4389-4394, 2003). In addition, data on class I selectivity of benzamideHDIs are emerging. MS-275 inhibited class I HDAC1 and 3 with IC₅₀=0.51μM and 1.7 μM, respectively. In contrast class II HDACs 4, 6, 8 and 10were inhibited with IC₅₀ values of >100 μM, >100M, 82.511M and 94.7 μM,respectively (Tatamiya et al, AACR Annual Meeting 2004, Abstract #2451).So far it is not clear if specificity towards HDAC class I or II enzymesor a defined single isoenzyme should be superior regarding therapeuticefficacy and index.

Clinical studies in cancer with HDAC inhibitors are on-going, namelywith SAHA (Merck Inc.), Valproic acid, FK228/Depsipeptide (GloucesterPharmaceuticals/NCl), MS275 (Berlex-Schering), NVP LBH-589 (Novartis),PXD-101 (Topotarget/Curagen), MGCD0103 (methylgene Inc.) andPivaloyloxymethylbutyrate/Pivanex (Titan Pharmaceuticals). These studiesshowed first evidence of clinical efficacy, highlighted recently bypartial and complete responses with FK228/Depsipeptide in patients withperipheral T-cell lymphoma (Plekarz et al. Blood, 98, 2865-2868, 2001)and diffuse large B-cell lymphoma by SAHA (Kelly et al. J. Clin. Oncol.23, 3923-3931, 2005).

Recent publications also showed possible medical use of HDAC inhibitorsin disease different to cancer. These diseases include systemic lupuserythematosus (Mishra et al. J Clin Invest 111, 539-552, 2003; Reilly etal. J. Immunol. 173, 4171-4178, 2004), rheumatoid arthritis (Chung etal. Mol Therapy 8, 707-717, 2003; Nishida et al. Arthritis &Rheumatology 50, 3365-3376, 2004), inflammatory diseases (Leoni et al.Proc Natl Acad Sci USA 99, 2995-3000, 2002) and neurodegenerativediseases like Huntington's disease (Steffan et al. Nature 413, 739-743,2001, Hockly et al. Proc Natl Acad Sci USA 100(4):2041-6, 2003).

Cancer chemotherapy was established based on the concept that cancercells with uncontrolled proliferation and a high proportion of cells inmitosis are killed preferentially. Standard cancer chemotherapeuticdrugs finally kill cancer cells upon induction of programmed cell death(“apoptosis”) by targeting basic cellular processes and molecules,namely RNA/DNA (alkylating and carbamylating agents, platin analogs andtopoisomerase inhibitors), metabolism (drugs of this class are namedanti-metabolites) as well as the mitotic spindle apparatus (stabilizingand destabilizing tubulin inhibitors). Inhibitors of histonedeacetylases (HDIs) constitute a new class of anti cancer drugs withdifferentiation and apoptosis inducing activity. By targeting histonedeacetylases, HDIs effect histone (protein) acetylation and chromatinstructure, inducing a complex transcriptional reprogramming, exemplifiedby reactivation of tumor suppressor genes and repression of oncogenes.Beside effecting acetylation of N-terminallysine residues in corehistone proteins, non-histone targets important for cancer cell biologylike heat-shock-protein 90 (Hsp90) or the p53 tumor suppressor proteinexist. The medical use of HDIs might not be restricted to cancertherapy, since efficacy in models for inflammatory diseases, rheumatoidarthritis and neurodegeneration was shown.

Benzoyl or acetyl substituted pyrrolyl propenamides are described in thepublic literature as HDAC-inhibitors, whereas the connectivity of theacyl-group is at position 2 or 3 of the pyrrole scaffold. (Mai et al.,Journal Med. Chem. 2004, Vol. 47, No. 5, 1098-1109; or Ragno et al.,Journal Med. Chem. 2004, Vol. 47, No. 5, 1351-1359). Further pyrrolylsubstituted hydroxamic acid derivatives are described in U.S. Pat. No.4,960,787 as lipoxygenase inhibitors or in U.S. Pat. No. 6,432,999 ascyclooxygenase inhibitors or in EP570594 as inhibitors of cell growth.

Various compounds, which are said to be HDAC inhibitors, are reported inWO 01/38322; WO 03/024448; US 2005/0234033; Journal Med. Chem. 2003,Vol. 46, No. 24, 5097-5116; Journal Med. Chem. 2003, Vol. 46, No. 4,512-524; Journal Med. Chem. 2003, Vol. 46, No. 5, 820-830; and inCurrent Opinion Drug Discovery 2002, Vol. 5, 487-499.

N-Sulphonylpyrrole derivatives are described as HDAC inhibitors in theinternational application WO 2005/087724, the disclosure of which isincorporated herein by reference.

There remains a need in the art for new, well tolerated and moreefficacious inhibitors of HDACs.

DESCRIPTION OF THE INVENTION

It has now been found that the N-sulphonylpyrrole derivatives, which aredescribed in greater details below, differ profoundly from prior artcompounds and are effective inhibitors of histone deacetylases and havesurprising and particularly advantageous properties.

In addition and based on the foregoing, it has also been found, thatcertain salts of those N-sulphonylpyrrole derivatives have surprisingand particularly advantageous properties, e.g. being crystallinematerials which possess useful properties.

The invention thus relates, in a first aspect (aspect 1), to compoundsof formula I

in which

-   R1 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,-   R2 is hydrogen or 1-4C-alkyl,-   R3 is hydrogen or 1-4C-alkyl,-   R4 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,-   R5 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,-   R6 is -T1-Q1, in which-   T1 is a bond, or 1-4C-alkylene,-   Q1 is Ar1, Aa1, Hh1, or Ah1, in which-   Ar1 is phenyl, or R61- and/or R62-substituted phenyl, in which-   R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which    either-   T2 is a bond, and-   R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl,    1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in    which-   Har1 is optionally substituted by R6111 and/or R6112, and is a    monocyclic or fused bicyclic 5 to 10-membered unsaturated    heteroaromatic ring comprising one to three heteroatoms, each of    which is selected from the group consisting of nitrogen, oxygen and    sulfur, in which-   R6111 is halogen, or 1-4C-alkyl,-   R6112 is 1-4C-alkyl, and-   R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or    hydroxy-2-4C-alkyl,-   or R611 and R612 together and with inclusion of the nitrogen atom,    to which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino,    S,S-dioxo-thiomorpholino, piperidino, pyrrolidino, piperazino, or    4N-(1-4C-alkyl)-piperazino,    or-   T2 is 1-4C-alkylene, or 2-4C-alkylene interrupted by oxygen, and-   R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl,    1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or-   Har1-1-4C-alkyl, in which-   Har1 is optionally substituted by R6111 and/or R6112, and is a    monocyclic or fused bicyclic 5 to 10-membered unsaturated    heteroaromatic ring comprising one to three heteroatoms, each of    which is selected from the group consisting of nitrogen, oxygen and    sulfur, in which-   R6111 is halogen, or 1-4C-alkyl,-   R6112 is 1-4C-alkyl, and-   R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or    hydroxy-2-4C-alkyl,-   or R611 and R612-together and with inclusion of the nitrogen atom,    to which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino,    S,S-dioxo-thiomorpholino, piperidino, pyrrolidino, piperazino,    4N-(1-4C-alkyl)-piperazino, imidazolo, pyrrolo or pyrazolo,-   R62 is 1-4C-alkyl, 1-4C-alkoxy, halogen, cyano,    1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonylamino, or    1-4C-alkylsulphonylamino,-   Aa1 is a bisaryl radical made up of two aryl groups,    -   which are selected independently from a group consisting of        phenyl and naphthyl, and    -   which are linked together via a single bond,-   Hh1 is a bisheteroaryl radical made up of two heteroaryl groups,    -   which are selected independently from a group consisting of        monocyclic 5 or 6-membered heteroaryl radicals comprising one or        two heteroatoms, each of which is selected from the group        consisting of nitrogen, oxygen and sulfur, and    -   which are linked together via a single bond,-   Ah1 is a heteroaryl-aryl radical or an aryl-heteroaryl radical made    up of a heteroaryl group selected from a group consisting of    monocyclic 5- or 6-membered heteroaryl radicals comprising one or    two heteroatoms, each of which is selected from the group consisting    of nitrogen, oxygen and sulfur, and an aryl group selected from a    group consisting of phenyl and naphthyl, whereby said heteroaryl and    aryl groups are linked together via a single bond,-   R7 is hydroxyl, or Cyc1, in which-   Cyc1 is a ring system of formula Ia

in which

-   A is C (carbon),-   B is C (carbon),-   R71 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,-   R72 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,-   M with inclusion of A and B is either a ring Ar2 or a ring Har2, in    which-   Ar2 is a benzene ring,-   Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic    ring comprising one to three heteroatoms, each of which is selected    from the group consisting of nitrogen, oxygen and sulfur,    and the salts of these compounds.

The invention relates, in a second aspect (aspect 2), to compounds offormula I in which

-   R1 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,-   R2 is hydrogen or 1-4C-alkyl,-   R3 is hydrogen or 1-4C-alkyl,-   R4 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,-   R5 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,-   R6 is -T1-Q1, in which-   T1 is a bond, or 1-4C-alkylene,-   Q1 is Ar1, Aa1, Hh1, or Ah1, in which-   Ar1 is phenyl, or R61- and/or R62-substituted phenyl, in which-   R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which-   T2 is a bond, 1-4C-alkylene, or 2-4C-alkylene interrupted by oxygen,-   R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl,    1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in    which-   Har1 is optionally substituted by R6111 and/or R6112, and is a    monocyclic or fused bicyclic 5- to 10-membered unsaturated    heteroaromatic ring comprising one to three heteroatoms, each of    which is selected from the group consisting of nitrogen, oxygen and    sulfur, in which-   R6111 is halogen, or 1-4C-alkyl,-   R6112 is 1-4C-alkyl,-   R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or    hydroxy-2-4C-alkyl,-   R62 is 1-4C-alkyl, 1-4C-alkoxy, halogen, cyano,    1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonylamino, or    1-4C-alkylsulphonylamino,-   Aa1 is a bisaryl radical made up of two aryl groups,    -   which are selected independently from a group consisting of        phenyl and naphthyl, and    -   which are linked together via a single bond,-   Hh1 is a bisheteroaryl radical made up of two heteroaryl groups,    -   which are selected independently from a group consisting of        monocyclic 5- or 6-membered heteroaryl radicals comprising one        or two heteroatoms, each of which is selected from the group        consisting of nitrogen, oxygen and sulfur, and    -   which are linked together via a single bond,-   Ah1 is a heteroaryl-aryl radical or an aryl-heteroaryl radical made    up of a heteroaryl group selected from a group consisting of    monocyclic 5- or 6-membered heteroaryl radicals comprising one or    two heteroatoms, each of which is selected from the group consisting    of nitrogen, oxygen and sulfur, and an aryl group selected from a    group consisting of phenyl and naphthyl, whereby said heteroaryl and    aryl groups are linked together via a single bond,-   R7 is hydroxyl, or Cyc1, in which-   Cyc1 is a ring system of formula Ia

in which

-   A is C (carbon),-   B is C (carbon),-   R71 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,-   R72 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,-   M with inclusion of A and B is either a ring Ar2 or a ring Har2, in    which-   Ar2 is a benzene ring,-   Har2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic    ring comprising one to three heteroatoms, each of which is selected    from the group consisting of nitrogen, oxygen and sulfur,    and the salts of these compounds.

The invention relates, in a third aspect (aspect 3), to certain salts ofthe compounds of formula I with hydrochloric acid, and to crystallineforms thereof.

In more detail, aspect 3 of this invention refers to salts of a compoundselected from

-   (E)-(E)-N-hydroxy-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-amino)-methyl)-benzene    sulfonyl]-1H-pyrrol-3-yl)-acrylamide,-   (E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acryl    amide, and-   (E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide    with hydrochloric acid,    their hydrates and to crystalline forms of these salts and hydrates.

1-4C-Alkyl represents a straight-chain or branched alkyl radical having1 to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably theethyl and methyl radicals.

2-4C-Alkyl represents a straight-chain or branched alkyl radical having2 to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably theethyl and propyl radicals.

1-4C-Alkylene is a branched or, particularly, straight chain alkyleneradical having 1 to 4 carbon atoms. Examples which may be mentioned arethe methylene (—CH₂—), ethylene (—CH₂—CH₂—), trimethylene(—CH₂—CH₂—CH₂—) and the tetramethylene (—CH₂—CH₂—CH₂—CH₂—) radical.2-4C-Alkylene interrupted by oxygen stands for a straight chain alkyleneradical having 1 to 4 carbon atoms which is suitably interrupted by anoxygen atom such as, for example, the [—CH₂—CH₂—O—CH₂—CH₂—] radical.

1-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyand methoxy radicals.

1-4C-Alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkylradicals, which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the methoxymethyl, themethoxyethyl and the isopropoxyethyl radicals, particularly the2-methoxyethyl and the 2-isopropoxyethyl radicals.

1-4C-Alkoxy-2-4C-alkyl represents one of the abovementioned 2-4C-alkylradicals, which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the methoxyethyl,ethoxyethyl and the isopropoxyethyl radicals, particularly the2-methoxyethyl, the 2-ethoxyethyl and the 2-isopropoxyethyl radicals.

Hydroxy-2-4C-alkyl represents one of the abovementioned 2-4C-alkylradicals, which is substituted by a hydroxy radical. An example whichmay be mentioned is the 2-hydroxyethyl or the 3-hydroxypropyl radical.

Phenyl-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, which is substituted by a phenyl radical. Examples which maybe mentioned are the benzyl and the phenethyl radicals.

Halogen within the meaning of the invention is bromine or, inparticular, chlorine or fluorine.

1-4C-Alkylcarbonyl represents a radical which, in addition to thecarbonyl group, contains one of the abovementioned 1-4C-alkyl radicals.An example which may be mentioned is the acetyl radical.

1-4C-Alkylcarbonylamino represents an amino radical which is substitutedby one of the abovementioned 1-4C-alkylcarbonyl radicals. An examplewhich may be mentioned is the acetamido radical [CH₃C(O)—NH—].

1-4C-Alkylsulphonylamino is, for example, the propylsulfonylamino[C₃H₇S(O)₂NH—], the ethylsulfonylamino [C₂H₅S(O)₂NH—] and themethylsulfonylamino [CH₃S(O)₂NH—] radical.

Aa1 is a bisaryl radical made up of two aryl groups,

which are selected independently from a group consisting of phenyl andnaphthyl, andwhich are linked together via a single bond.

Aa1 may include, without being restricted thereto, the biphenyl radical,e.g. the 1,1′-biphen-4-yl or 1,1′-biphen-3-yl radical.

Hh1 is a bisheteroaryl radical made up of two heteroaryl groups,

which are selected independently from a group consisting of monocyclic5- or 6-membered heteroaryl radicals comprising one or two heteroatoms,each of which is selected from the group consisting of nitrogen, oxygenand sulfur, andwhich are linked together via a single bond.

Hh1 may include, without being restricted thereto, the bithiophenyl,bipyridyl, pyrazolyl-pyridinyl (particularly pyrazol-1-yl-pyridinyl),imidazolyl-pyridinyl (particularly imidazol-1-yl-pyridinyl) or thepyridinyl-thiophenyl radical, e.g. the 5-(pyridin-2-yl)-thiophen-2-ylradical.

In a special detail, exemplary Hh1 radicals may includepyridinyl-thiophenyl, e.g. 5-(pyridin-2-yl)-thiophen-2-yl.

Ah1 is a heteroarylaryl radical or an arylheteroaryl radical made up ofa heteroaryl group selected from a group consisting of monocyclic 5- or6-membered heteroaryl radicals comprising one or two heteroatoms, eachof which is selected from the group consisting of nitrogen, oxygen andsulfur, and an aryl group selected from a group consisting of phenyl andnaphthyl, whereby said heteroaryl and aryl groups are linked togethervia a single bond.

The Ah1 radical can be bonded either via said heteroaryl or via saidaryl moiety to the parent molecular group.

A particular embodiment of said Ah1 radicals refers to heteroaryl-phenylradicals, e.g. 3-(heteroaryl)-phenyl or 4-(heteroaryl)-phenyl radicals.

Ah1 may include, without being restricted thereto, the phenyl-thiophenylor phenyl-pyridyl radicals.

Alternatively, Ah1 may include, without being restricted thereto thefuranyl-phenyl, pyrazolyl-phenyl (e.g. pyrazol-1-yl-phenyl or1H-pyrazol-4-yl-phenyl), imidazolyl-phenyl (e.g. imidazol-1-yl-phenyl)or pyridinyl-phenyl radicals.

In a special detail, exemplary Ah1 radicals may include3-(pyrazolyl)-phenyl, 4-(pyrazolyl)-phenyl, 4-(pyridinyl)-phenyl or3-(pyridinyl)-phenyl.

In a further special detail, exemplary Ah1 radicals may include3-(pyrazol-1-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl,4-(pyridin-4-yl)-phenyl, 3-(pyridin-4-yl)-phenyl,4-(pyridin-3-yl)-phenyl, 3-(pyridin-3-yl)-phenyl,3-(1H-pyrazol-4-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl.

It is to be stated, that each of the radicals Hh1 and Ah1 is bondedpreferably via a ring carbon atom to the moiety T1.

Har1 is optionally substituted by R6111 and/or R6112, and is amonocyclic or fused bicyclic 5- to 10-membered unsaturated(heteroaromatic) heteroaryl radical comprising one to three heteroatoms,each of which is selected from the group consisting of nitrogen, oxygenand sulfur. In one detail, fused, in particular benzo-fused, bicyclic 9-or 10-membered heteroaryl radicals comprising one to three, inparticular one or two, heteroatoms, each of which is selected from thegroup consisting of nitrogen, oxygen and sulfur, are to be mentioned.Examples of Har1 include, without being restricted thereto, thiophenyl,furanyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; and, in particular,the stable benzo-fused derivatives thereof, such as e.g.benzothiophenyl, benzofuranyl, indolyl, benzoxazolyl, benzothiazolyl,indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl,benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,phthalazinyl or cinnolinyl; and purinyl, indolizinyl, naphthyridinyl orpteridinyl.

In a special detail, exemplary Har1 radicals may include pyridinyl,benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl and indolyl,such as e.g. pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,benzimidazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl, benzofuran-3-yl,benzothiophen-2-yl, benzothiophen-3-yl, indol-2-yl, indol-3-yl orindol-5-yl.

In a further special detail, an exemplary Har1 radical may be indolyl,such as e.g. indol-2-yl, indol-3-yl or indol-5-yl.

Yet in a further special detail, an exemplary Har1 radical may bepyridinyl, such as e.g. pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

As further examples of Har1, the R6111- and/or R6112-substitutedderivatives of the above-mentioned exemplary Har1 radicals may bementioned.

Har1-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, such as e.g. methyl, ethyl or propyl, substituted by one ofthe abovementioned Har1 radicals, such as e.g. imidazolyl,benzimidazolyl, indolyl or pyrrolyl and the like or the substitutedderivatives thereof. As examples may be mentioned, without beingrestricted thereto, pyridinylmethyl (e.g. pyridin-3-yl-methyl),imidazolylmethyl, pyrrolylmethyl, 2-imidazolylethyl (e.g.2-imidazol-5-yl-ethyl), 2-pyridinylethyl, 3-(benzofuran-2-yl)propyl,3-(benzimidazol-2-yl)propyl, 2-indolylethyl (e.g. 2-indol-2-yl-ethyl or2-indol-3-yl-ethyl), indolylmethyl (e.g. indol-2-yl-methyl,indol-3-yl-methyl or indol-5-yl-methyl), 2-benzimidazolylethyl (e.g.2-benzimidazol-2-ylethyl), benzimidazolylmethyl (e.g.benzimidazol-2-yl-methyl), and the like.

In a special detail, exemplary Har1-1-4C-alkyl radicals may includepyridinylmethyl (e.g. pyridin-3-yl-methyl, pyridin-4-yl-methyl orpyridin-4-yl-methyl), 2-pyridinylethyl (e.g. 2-pyridin-3-yl-ethyl),indolylmethyl (e.g. indol-2-yl-methyl, indol-3-yl-methyl orindol-5-yl-methyl) or 2-indolylethyl (e.g. 2-indolyl-2-yl-ethyl or2-indolyl-3-yl-ethyl).

In a further special detail, exemplary Har1-1-4C-alkyl radicals mayinclude pyridin-3-yl-methyl, pyridin-4-yl-methyl, 2-pyridin-3-yl-ethyl,indol-2-yl-methyl, indol-3-yl-methyl, indol-5-yl-methyl,2-indolyl-2-yl-ethyl or 2-indolyl-3-yl-ethyl.

In the context of the radical Har1-1-4C-alkyl, it is to be stated, thatthe portion Har1 is bonded preferably via a ring carbon atom to the1-4C-alkyl moiety.

One embodiment of those Har1-1-4C-alkyl radicals, in which the Har1moiety is a fused bicyclic ring containing a benzene ring, refers tothose radicals, in which the Har1 moiety is preferably bonded to the1-4C-alkyl moiety via a carbon ring atom of the ring comprising one ormore heteroatoms.

Another embodiment of those Har1-1-4C-alkyl radicals, in which the Har1moiety is a fused bicyclic ring containing a benzene ring, refers tothose radicals, in which the Har1 moiety is preferably bonded to the1-4C-alkyl moiety via a carbon ring atom of the benzene ring.

Har2 stands for a monocyclic 5- or 6-membered unsaturated heteroaromaticring comprising one to three heteroatoms, each of which is selected fromthe group consisting of nitrogen, oxygen and sulfur. Har2 may include,without being restricted thereto, thiophene, oxazole, isoxazole,thiazole, isothiazole, imidazole, pyrazole, triazole, thiadiazole,oxadiazole, pyridine, pyrimidine, pyrazine or pyridazine.

In a special detail, an exemplary Har2 radical may be pyridine.

Cyc1 stands for a ring system of formula Ia, which is bonded to thenitrogen atom of the carboxamide group via the moiety A. Cyc1 mayinclude, without being restricted thereto, 2-aminophenyl substituted byR71 and/or R72.

Naphthyl, alone or as part of another group, includes naphthalen-1-yland naphthalen-2-yl.

In the meaning of the present invention, it is to be understood, that,when two structural portions of the compounds according to thisinvention are linked via a constituent which has the meaning “bond”,then said two portions are directly attached to another via a singlebond.

In general, unless otherwise mentioned the heterocyclic groups mentionedherein refer to all of the possible isomeric forms thereof.

The heterocyclic groups mentioned herein refer, unless otherwise noted,in particular to all of the possible positional isomers thereof.

Thus, for example, the term pyridyl or pyridinyl, alone or as part ofanother group, includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

Constituents which are optionally substituted as stated herein, may besubstituted, unless otherwise noted, at any possible position.

The carbocyclic groups, alone or as part of other groups, mentionedherein may be substituted by their given substituents or parentmolecular groups, unless otherwise noted, at any substitutable ringcarbon atom.

The heterocyclic groups, alone or as part of other groups, mentionedherein may be substituted by their given substituents or parentmolecular groups, unless otherwise noted, at any possible position, suchas e.g. at any substitutable ring carbon or ring nitrogen atom.

Rings containing quaternizable imino-type ring nitrogen atoms (—N═) maybe preferably not quaternized on these imino-type ring nitrogen atoms bythe mentioned substituents or parent molecular groups.

Any heteroatom of a heterocyclic ring with unsatisfied valencesmentioned herein is assumed to have the hydrogen atom(s) to satisfy thevalences.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

Suitable salts for compounds of the formula I—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerableinorganic and organic acids and bases customarily used in pharmacy.Those suitable are, on the one hand, water-insoluble and, particularly,water-soluble acid addition salts with acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are—depending on substitution—alsosuitable. As examples of salts with bases are mentioned the lithium,sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium,meglumine or guanidinium salts, here, too, the bases being employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Salts which are unsuitable for pharmaceutical uses but which can beemployed, for example, for the isolation, purification or preparation offree compounds of formula I or their pharmaceutically acceptable salts,are also included.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of formula I of theinvention as well as their salts may contain, e.g. when isolated incrystalline form, varying amounts of solvents. Included within the scopeof the invention are therefore all solvates and in particular allhydrates of the compounds of formula I as well as all solvates and inparticular all hydrates of the salts of the compounds of formula I.

In one embodiment of this invention, salts of the compounds of formula Iinclude salts of compounds of formula I with hydrochloric acid.

Furthermore, the invention includes all conceivable polymorphic forms ofthe compounds of the present invention in pure form as well as anymixtures thereof.

The substituents R61 and R62 of compounds of formula I can be attachedin the ortho, meta or para position with respect to the binding positionin which the phenyl ring is bonded to T1, whereby preference is given tothe attachment in the meta or, particularly, in the para position.

In another embodiment, Ar1 is phenyl which is mono-substituted by R61,whereby preference is given to the attachment of R61 in the meta or paraposition with respect to the binding position in which the phenyl ringis bonded to T1.

In yet another embodiment, Ar1 is phenyl which is mono-substituted byR61, whereby preference is given to the attachment of R61 in the paraposition with respect to the binding position in which the phenyl ringis bonded to T1.

In still yet another embodiment, Ar1 is phenyl which is mono-substitutedby R61, whereby preference is given to the attachment of R61 in the metaposition with respect to the binding position in which the phenyl ringis bonded to T1.

Compounds according to aspect 1 of the present invention more worthy tobe mentioned are those compounds of formula I

in which

-   R1 is hydrogen, or 1-4C-alkyl,-   R2 is hydrogen, or 1-4C-alkyl,-   R3 is hydrogen, or 1-4C-alkyl,-   R4 is hydrogen, or 1-4C-alkyl,-   R5 is hydrogen, or 1-4C-alkyl,-   R6 is -T1-Q1, in which-   T1 is a bond, or 1-4C-alkylene,-   Q1 is Ar1, Aa1, Hh1, or Ah1, in which-   Ar1 is phenyl, or R61-substituted phenyl, in which-   R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which    either-   T2 is a bond,-   R611 is hydrogen, 1-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl,    in which-   Har1 is either    -   a monocyclic 5-membered unsaturated heteroaromatic ring        comprising one, two or three heteroatoms, each of which is        selected from the group consisting of nitrogen, oxygen and        sulfur, or    -   a monocyclic 6-membered unsaturated heteroaromatic ring        comprising one or two nitrogen atoms, or    -   a fused bicyclic 9-membered unsaturated heteroaromatic ring        comprising one, two or three heteroatoms, each of which is        selected from the group consisting of nitrogen, oxygen and        sulfur, or    -   a fused bicyclic 10-membered unsaturated heteroaromatic ring        comprising one or two heteroatoms, each of which is selected        from the group consisting of nitrogen, oxygen and sulfur, and-   R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-4C-alkyl,-   or R611 and R612 together and with inclusion of the nitrogen atom,    to which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino,    or-   T2 is 1-4C-alkylene,-   R611 is hydrogen, 1-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl,    in which-   Har1 is either    -   a monocyclic 5-membered unsaturated heteroaromatic ring        comprising one, two or three heteroatoms, each of which is        selected from the group consisting of nitrogen, oxygen and        sulfur, or    -   a monocyclic 6-membered unsaturated heteroaromatic ring        comprising one or two nitrogen atoms, or    -   a fused bicyclic 9-membered unsaturated heteroaromatic ring        comprising one, two or three heteroatoms, each of which is        selected from the group consisting of nitrogen, oxygen and        sulfur, or    -   a fused bicyclic 10-membered unsaturated heteroaromatic ring        comprising one or two heteroatoms, each of which is selected        from the group consisting of nitrogen, oxygen and sulfur, and-   R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-4C-alkyl,-   or R611 and R612 together and with inclusion of the nitrogen atom,    to which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino,-   Aa1 is a biphenyl radical,-   Hh1 is a bipyridyl, pyrazolyl-pyridinyl, imidazolyl-pyridinyl, or    pyridinyl-thiophenyl radical,-   Ah1 is a pyridinyl-phenyl, pyrazolyl-phenyl, or imidazolyl-phenyl    radical,-   R7 is hydroxyl, or 2-aminophenyl,    and the salts of these compounds.

Compounds according to aspect 2 of the present invention more worthy tobe mentioned are those compounds of formula I

in whichR1 is hydrogen, or 1-4C-alkyl,R2 is hydrogen, or 1-4C-alkyl,R3 is hydrogen, or 1-4C-alkyl,R4 is hydrogen, or 1-4C-alkyl,R5 is hydrogen, or 1-4C-alkyl,R6 is -T1-Q1, in whichT1 is a bond, or 1-4C-alkylene,Q1 is Ar1, or Aa1, in whichAr1 is phenyl, or R61-substituted phenyl, in whichR61 is 1-4C-alkyl, or -T2-N(R611)R612, in whichT2 is a bond, or 1-4C-alkylene,R611 is hydrogen, 1-4C-alkyl, or Har1-1-4C-alkyl, in whichHar1 is imidazolyl, benzimidazolyl, indolyl or pyrrolyl,R612 is hydrogen, or 1-4C-alkyl,Aa1 is a biphenyl radical,R7 is hydroxyl, or 2-aminophenyl,and the salts of these compounds.

Compounds according to aspect 1 of the present invention in particularworthy to be mentioned are those compounds of formula I

in which

-   R1 is hydrogen,-   R2 is hydrogen,-   R3 is hydrogen,-   R4 is hydrogen,-   R5 is hydrogen,-   R6 is -T1-Q1, Aa1, Hh1, or Ah1, in which-   T1 is a bond, or 1-2C-alkylene,-   Q1 is Ar1, in which-   Ar1 is phenyl, or R61-substituted phenyl, in which-   R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which    either-   T2 is a bond,-   R611 is hydrogen, 1-4C-alkyl, phenyl-1-2C-alkyl, or Har1-1-2C-alkyl,    in which-   Har1 is pyridinyl, benzimidazolyl, benzoxazolyl, benzofuranyl,    benzothiophenyl or indolyl, and-   R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-3C-alkyl,-   or R611 and R612 together and with inclusion of the nitrogen atom,    to which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino,    or-   T2 is 1-2C-alkylene,-   R611 is hydrogen, 1-4C-alkyl, phenyl-1-2C-alkyl, or Har1-1-2C-alkyl,    in which Har1 is pyridinyl, benzimidazolyl, benzoxazolyl,    benzofuranyl, benzothiophenyl or indolyl, and

R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-3C-alkyl,

-   or R611 and R612 together and with inclusion of the nitrogen atom,    to which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino,-   Aa1 is a biphenyl radical,-   Hh1 is a bipyridyl, pyrazolyl-pyridinyl, imidazolyl-pyridinyl, or    pyridinyl-thiophenyl radical,-   Ah1 is a pyridinyl-phenyl, pyrazolyl-phenyl, or imidazolyl-phenyl    radical,-   R7 is hydroxyl, or 2-aminophenyl,    and the salts of these compounds.

Compounds according to aspect 2 of the present invention in particularworthy to be mentioned are those compounds of formula I in which

R1 is hydrogen,R2 is hydrogen,R3 is hydrogen,R4 is hydrogen,R5 is hydrogen,R6 is -T1-Q1, or biphenyl, in whichT1 is a bond, or 1-2C-alkylene,Q1 is Ar1, in whichAr1 is phenyl, or R61-substituted phenyl, in whichR61 is 1-4C-alkyl, or -T2-N(R611)R612, in whichT2 is a bond, or 1-2C-alkylene,R611 is 1-4C-alkyl, or Har1-1-2C-alkyl, in whichHar1 is benzimidazolyl or indolyl,

R612 is 1-4C-alkyl,

R7 is hydroxyl, or 2-aminophenyl,and the salts of these compounds.

Compounds according to aspect 1 of the present invention in moreparticular worthy to be mentioned are those compounds of formula I

in which

-   R1 is hydrogen,-   R2 is hydrogen,-   R3 is hydrogen,-   R4 is hydrogen,-   R5 is hydrogen,-   R6 is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which-   T1 is a bond,-   Q1 is Ar1, in which-   Ar1 is phenyl, or R61-substituted phenyl, in which-   R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which    either-   T2 is a bond,-   R611 is 1-4C-alkyl, and-   R612 is 1-4C-alkyl,    or-   T2 is 1-2C-alkylene,-   R611 is hydrogen, 1-4C-alkyl, phenyl-1-2C-alkyl, or Har1-1-2C-alkyl,    in which-   Har1 is pyridinyl, or indolyl, and-   R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-3C-alkyl,-   or R611 and R612 together and with inclusion of the nitrogen atom,    to which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino,-   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,-   Hh1 is a pyridinyl-thiophenyl radical,-   Ah1 is a 3-(pyridinyl)-phenyl, 3-(pyrazolyl)-phenyl,    4-(pyridinyl)-phenyl or 4-(pyrazolyl)-phenyl radical,-   R7 is hydroxyl, or 2-aminophenyl,    and the salts of these compounds.

Compounds according to aspect 2 of the present invention in moreparticular worthy to be mentioned are those compounds of formula I

in whichR1 is hydrogen,R2 is hydrogen,R3 is hydrogen,R4 is hydrogen,R5 is hydrogen,

R6 is -T1-Q1, biphenyl, or benzyl, in which

T1 is a bond,Q1 is Ar1, in whichAr1 is R61-substituted phenyl, in particular 4-(R61)-phenyl, in whichR61 is methyl, dimethylamino, or -T2-N(R611)R612, in whichT2 is methylene,R611 is methyl or 2-(indol-2-yl)ethyl,R612 is methyl,R7 is hydroxyl, or 2-aminophenyl,and the salts of these compounds.

Compounds according to aspect 1 of the present invention to beemphasized are those compounds of formula I

in which

-   R1 is hydrogen,-   R2 is hydrogen,-   R3 is hydrogen,-   R4 is hydrogen,-   R5 is hydrogen,-   R6 is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which-   T1 is a bond,-   Q1 is Ar1, in which-   Ar1 is phenyl, 3-(R61)-phenyl, or 4-(R61)-phenyl, in which-   R61 is methyl, or -T2-N(R611)R612, in which either-   T2 is a bond,-   R611 is methyl, and-   R612 is methyl,    or-   T2 is methylene,-   R611 is hydrogen, methyl, isobutyl, benzyl, Har1-methyl, or    2-(Har1)-ethyl in which-   Har1 is pyridinyl or indolyl, and-   R612 is hydrogen, methyl, or 2-hydroxy-ethyl,-   or R611 and R612 together and with inclusion of the nitrogen atom,    to which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino,-   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,-   Hh1 is a pyridinyl-thiophenyl radical,-   Ah1 is a 3-(pyridinyl)-phenyl, 3-(pyrazolyl)-phenyl,    4-(pyridinyl)-phenyl or 4-(pyrazolyl)-phenyl radical,-   R7 is hydroxyl, or 2-aminophenyl,    and the salts of these compounds.

Compounds according to aspect 1 of the present invention to be moreemphasized are those compounds of formula I

in which

-   R1 is hydrogen,-   R2 is hydrogen,-   R3 is hydrogen,-   R4 is hydrogen,-   R5 is hydrogen,-   R6 is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which-   T1 is a bond,-   Q1 is Ar1, in which-   Ar1 is phenyl, 3-(R61)-phenyl, or 4-(R61)-phenyl, in which-   R61 is methyl, or -T2-N(R611)R612, in which either-   T2 is a bond,-   R611 is methyl, and-   R612 is methyl,    or-   T2 is methylene,-   R611 is hydrogen, methyl, isobutyl, benzyl, Har1-methyl, or    2-(Har1)-ethyl in which-   Har1 is pyridin-3-yl, pyridin-4-yl, indol-2-yl, indol-3-yl or    indol-5-yl, and-   R612 is hydrogen, methyl, or 2-hydroxy-ethyl,-   or R611 and R612 together and with inclusion of the nitrogen atom,    to which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino,-   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,-   Hh1 is 5-(pyridin-2-yl)-thiophen-2-yl,-   Ah1 is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl,    3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl,    4-(pyridin-3-yl)-phenyl, 4-(pyridin-4-yl)-phenyl,    4-(pyrazol-1-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl,-   R7 is hydroxyl, or 2-aminophenyl,    and the salts of these compounds.

Compounds according to aspect 1 of the present invention to be inparticular emphasized are those compounds of formula I

in which

-   R1 is hydrogen,-   R2 is hydrogen,-   R3 is hydrogen,-   R4 is hydrogen,-   R5 is hydrogen,-   R6 is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which is a bond,-   Q1 is Ar1, in which-   Ar1 is phenyl, 3-(R61)-phenyl, or 4-(R61)-phenyl, in which-   R61 is methyl, or -T2-N(R611)R612, in which    either-   T2 is a bond,-   R611 is methyl, and-   R612 is methyl,    or-   T2 is methylene,-   R611 is hydrogen, isobutyl, benzyl, Har1-methyl, or 2-(Har1)-ethyl,    in which is pyridin-3-yl, pyridin-4-yl, indol-2-yl, indol-3-yl or    indol-5-yl, and is hydrogen,    or-   T2 is methylene,-   is methyl, or 2-(Har1)-ethyl, in which is indol-2-yl, and-   R612 is methyl,    or-   T2 is methylene,-   R611 is 2-(Har1)-ethyl, in which-   Har1 is indol-2-yl, and-   R612 is 2-hydroxy-ethyl,    or-   T2 is methylene, and-   R611 and R612 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino,-   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,-   Hh1 is 5-(pyridin-2-yl)-thiophen-2-yl,-   Ah1 is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl,    3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl,    4-(pyridin-3-yl)-phenyl, 4-(pyridin-4-yl)-phenyl,    4-(pyrazol-1-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl,-   R7 is hydroxyl,    and the salts of these compounds.

Yet compounds according to aspect 1 of the present invention to be inparticular emphasized are those compounds of formula I

in which

-   R1 is hydrogen,-   R2 is hydrogen,-   R3 is hydrogen,-   R4 is hydrogen,-   R5 is hydrogen,-   R6 is -T1-Q1, Aa1, Hh1, Ah1, or benzyl, in which-   T1 is a bond,-   Q1 is Ar1, in which-   Ar1 is phenyl, 3-(R61)-phenyl, or 4-(R61)-phenyl, in which-   R61 is methyl, or -T2-N(R611)R612, in which    either-   T2 is a bond,-   R611 is methyl, and-   R612 is methyl,    or-   T2 is methylene,-   R611 is hydrogen, isobutyl, benzyl, Har1-methyl, or 2-(Har1)-ethyl,    in which-   Har1 is pyridin-3-yl, pyridin-4-yl, indol-3-yl, or indol-5-yl, and-   R612 is hydrogen,    or-   T2 is methylene,-   R611 is methyl, or 2-(Har1)-ethyl, in which-   Har1 is indol-2-yl, and-   R612 is methyl,    or-   T2 is methylene,-   R611 is 2-(Har1)-ethyl, in which-   Har1 is indol-2-yl, and-   R612 is 2-hydroxy-ethyl,    or-   T2 is methylene, and-   R611 and R612 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is morpholino,-   Aa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl,-   Hh1 is 5-(pyridin-2-yl)-thiophen-2-yl,-   Ah1 is 3-(pyridin-3-yl)-phenyl, 3-(pyridin-4-yl)-phenyl,    3-(pyrazol-1-yl)-phenyl, 3-(1H-pyrazol-4-yl)-phenyl,    4-(pyridin-3-yl)-phenyl, 4-(pyridin-4-yl)-phenyl,    4-(pyrazol-1-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl,-   R7 is 2-aminophenyl,    and the salts of these compounds.

A special interest in the compounds according to the present inventionrefers to those compounds of this invention which are included—withinthe scope of this invention—by one or, when possible, a combination ofmore of the following embodiments:

An embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R1, R2, R3, R4 and R5are all hydrogen.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R7 is hydroxyl.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R7 is Cyc1, whereby ina subembodiment thereof. Cyc1 is 2-phenyl.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R7 is 2-aminophenyl.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R6 is Aa1.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R6 is Ar1 or —CH₂—Ar1.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which Ar1 is R61-substitutedphenyl.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which Ar1 is phenylmonosubstituted by R61 in the meta position with respect to the bindingposition in which the phenyl ring is bonded to T1.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which Ar1 is phenylmonosubstituted by R61 in the para position with respect to the bindingposition in which the phenyl ring is bonded to T1.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R6 is Hh1.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R6 is Ah1.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which T2 is a bond.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which T2 is 1-4C-alkylene,such as e.g. methylene.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which

R6 is Ar1, in whichAr1 is R61-substituted phenyl, in whichR61 is -T2-N(R611)R612, in whichT2 is a bond.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which

R6 is Ar1, in whichAr1 is R61-substituted phenyl, in whichR61 is -T2-N(R611)R612, in whichT2 is 1-4C-alkylene, such as e.g. methylene.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Ar1, in whichAr1 is any one selected from the group consisting of3-methyl-phenyl, 4-methyl-phenyl, 3-dimethylamino-phenyl,4-dimethylamino-phenyl, 3-aminomethyl-phenyl, 4-aminomethyl-phenyl,3-(morpholin-4-yl-methyl)-phenyl, 4-(morpholin-4-yl-methyl)-phenyl,3-(N-benzylamino-methyl)-phenyl, 3-(N-isobutylamino-methyl)-phenyl,4-(N-benzylamino-methyl)-phenyl, 4-(N-isobutylamino-methyl)-phenyl,3-[N-(pyridinylmethyl)amino-methyl]-phenyl,3-[N-(indolylmethyl)amino-methyl]-phenyl,4-[N-(pyridinylmethyl)amino-methyl]-phenyl,4-[N-(indolylmethyl)amino-methyl]-phenyl,3-(N,N-dimethylamino-methyl)-phenyl,4-(N,N-dimethylamino-methyl)-phenyl,3-[N,N-(2-indolylethyl)-methyl-amino-methyl]-phenyl,4-[N,N-(2-indolylethyl)-methyl-amino-methyl]-phenyl,3-[N,N-(2-indolylethyl)-(2-hydroxyethyl)-amino-methyl]-phenyl, and4-[N,N-(2-indolyl ethyl)-(2-hydroxyethyl)-amino-methyl]-phenyl.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Aa1, in whichAa1 is a biphenyl radical.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Hal, in whichHa1 is a pyridinyl-thiophenyl radical.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Ah1, in whichAh1 is a 3-(pyrazolyl)-phenyl, 4-(pyrazolyl)-phenyl,4-(pyridinyl)-phenyl, or 3-(pyridinyl)-phenyl radical.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R1, R2, R3, R4 and R5are all hydrogen, and R7 is hydroxyl.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R1, R2, R3, R4 and R5are all hydrogen, and R7 is Cyc1.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R1, R2, R3, R4 and R5are all hydrogen, and R7 is 2-aminophenyl.

A further embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which R1, R2, R3, R4 and R5are all hydrogen, and R7 is aminopyridyl.

A special embodiment of the compounds according to the present inventionrelates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Ar1, in whichAr1 is any one selected from the group consisting of3-methyl-phenyl, 4-methyl-phenyl, 3-dimethylamino-phenyl,4-dimethylamino-phenyl, 3-aminomethyl-phenyl, 4-aminomethyl-phenyl,3-(morpholin-4-yl-methyl)-phenyl, 4-(morpholin-4-yl-methyl)-phenyl,3-(N-benzylamino-methyl)-phenyl, 3-(N-isobutylamino-methyl)-phenyl,4-(N-benzylamino-methyl)-phenyl, 4-(N-isobutylamino-methyl)-phenyl,3-[N-(pyridin-3-yl-methyl)amino-methyl]-phenyl,3-[N-(pyridin-4-yl-methyl)amino-methyl]-phenyl,3-[N-(indol-5-yl-methyl)amino-methyl]-phenyl,3-[N-(indol-3-yl-methyl)amino-methyl]-phenyl,4-[N-(pyridin-3-yl-methyl)amino-methyl]-phenyl,4-[N-(pyridin-4-yl-methyl)amino-methyl]-phenyl,4-[N-(indol-5-yl-methyl)amino-methyl]-phenyl,4-[N-(indol-3-yl-methyl)amino-methyl]-phenyl,3-(N,N-dimethylamino-methyl)-phenyl,4-(N,N-dimethylamino-methyl)-phenyl,3{N,N-[2-(indol-2-yl)-ethyl]-methyl-amino-methyl}phenyl,4-{N,N-[2-(indol-2-yl)-ethyl]-methyl-amino-methyl}-phenyl,3{N,N-[2-(indol-2-yl)-ethyl]-(2-hydroxyethyl)-amino-methyl}-phenyl, and4-{N,N-[2-(indol-2-yl)-ethyl]-(2-hydroxyethyl)-amino-methyl}-phenyl, andR7 is hydroxyl,and the salts thereof.

Another special embodiment of the compounds according to the presentinvention relates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Aa1, in whichAa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl, andR7 is hydroxyl,and the salts thereof.

Another special embodiment of the compounds according to the presentinvention relates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Hal, in whichHa1 is 5-(pyridin-2-yl)-thiophen-2-yl, andR7 is hydroxyl,and the salts thereof.

Another special embodiment of the compounds according to the presentinvention relates to those compounds of formula I, in which

-   R1, R2, R3, R4 and R5 are all hydrogen, and-   R6 is Ah1, in which-   Ah1 is 3-(pyrazol-1-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl,    4-(pyridin-4-yl)-phenyl, 3-(pyridin-4-yl)-phenyl,    4-(pyridin-3-yl)-phenyl, 3-(pyridin-3-yl)-phenyl,    3-(1H-pyrazol-4-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl,-   R7 is hydroxyl,    and the salts thereof.

Another special embodiment of the compounds according to the presentinvention relates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Ar1, in whichAr1 is any one selected from the group consisting of3-methyl-phenyl, 4-methyl-phenyl, 3-dimethylamino-phenyl,4-dimethylamino-phenyl, 3-aminomethyl-phenyl, 4-aminomethyl-phenyl,3-(morpholin-4-yl-methyl)-phenyl, 4-(morpholin-4-yl-methyl)-phenyl,3-(N-benzylamino-methyl)-phenyl, 3-(N-isobutylamino-methyl)-phenyl,4-(N-benzylamino-methyl)-phenyl, 4-(N-isobutylamino-methyl)-phenyl,3-[N-(pyridin-3-yl-methyl)amino-methyl]-phenyl,3-[N-(pyridin-4-yl-methyl)amino-methyl]-phenyl,3-[N-(indol-5-yl-methyl)amino-methyl]-phenyl,3-[N-(indol-3-yl-methyl)amino-methyl]-phenyl,4-[N-(pyridin-3-yl-methyl)amino-methyl]-phenyl,4-[N-(pyridin-4-yl-methyl)amino-methyl]-phenyl,4-[N-(indol-5-yl-methyl)amino-methyl]-phenyl,4-[N-(indol-3-yl-methyl)amino-methyl]-phenyl,3-(N,N-dimethylamino-methyl)-phenyl,4-(N,N-dimethylamino-methyl)-phenyl,3{N,N-[2-(indol-2-yl)-ethyl]-methyl-amino-methyl}-phenyl,4-{N,N-[2-(indol-2-yl)-ethyl]-methyl-amino-methyl}-phenyl,3{N,N-[2-(indol-2-yl)-ethyl]-(2-hydroxyethyl)-amino-methyl}-phenyl, and4-{N,N-[2-(indol-2-yl)-ethyl]-(2-hydroxyethyl)-amino-methyl}-phenyl, andR7 is 2-aminophenyl,and the salts thereof.

Another special embodiment of the compounds according to the presentinvention relates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Aa1, in whichAa1 is 1,1′-biphen-4-yl or 1,1′-biphen-3-yl, andR7 is 2-aminophenyl,and the salts thereof.

Another special embodiment of the compounds according to the presentinvention relates to those compounds of formula I, in which

R1, R2, R3, R4 and R5 are all hydrogen, andR6 is Hal, in whichHa1 is 5-(pyridin-2-yl)-thiophen-2-yl, andR7 is 2-aminophenyl,and the salts thereof.

Another special embodiment of the compounds according to the presentinvention relates to those compounds of formula I, in which

-   R1, R2, R3, R4 and R5 are all hydrogen, and-   R6 is Ah1, in which-   Ah1 is 3-(pyrazol-1-yl)-phenyl, 4-(pyrazol-1-yl)-phenyl,    4-(pyridin-4-yl)-phenyl, 3-(pyridin-4-yl)-phenyl,    4-(pyridin-3-yl)-phenyl, 3-(pyridin-3-yl)-phenyl,    3-(1H-pyrazol-4-yl)-phenyl or 4-(1H-pyrazol-4-yl)-phenyl,-   R7 is 2-aminophenyl,    and the salts thereof.

Exemplary compounds according to this invention may include any oneselected from

-   1.    (E)-N-Hydroxy-3-[1-(toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-acrylamide-   2. N-Hydroxy-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylamide-   3.    (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide-   4.    (E)-3-[1-(4-Dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide-   5.    (E)-N-(2-Amino-phenyl)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide-   6.    (E)-N-(2-Amino-phenyl)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylamide-   7.    (E)-N-(2-Amino-phenyl)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide-   8.    (E)-N-(2-Amino-phenyl)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   9.    (E)-N-Hydroxy-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-amino)-methyl)-benzene    sulfonyl]-1H-pyrrol-3-yl)-acrylamide-   10.    (E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide-   11.    (E)-N-Hydroxy-3-[1-(4-{[(pyridin-3-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   12.    (E)-N-Hydroxy-3-[1-(4-{[(1H-indol-3-ylmethyl)-amino]-methyl}benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   13.    (E)-3-{1-[4-(Benzylamino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}N-hydroxy-acrylamide-   14.    (E)-N-Hydroxy-3-{1-[4-(isobutylamino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide-   15.    (E)-N-Hydroxy-3-[1-(4-{[(1H-indol-5-ylmethyl)-amino]-methyl}benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   16.    (E)-N-Hydroxy-3-[1-(4-{[(pyridin-4-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   17.    (E)-3-[1-(4-Aminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide-   18.    (E)-N-Hydroxy-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   19.    (E)-N-Hydroxy-3-[1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl]acrylamide-   20.    (E)-N-(2-Amino-phenyl)-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   21.    (E)-N-(2-Amino-phenyl)-3-[1-(4-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   22.    (E)-N-(2-Amino-phenyl)-3-{1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide-   23.    (E)-3-[1-(Biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide-   24.    (E)-N-Hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide-   25.    (E)-N-Hydroxy-3-[1-(4-pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   26.    (E)-N-(2-Amino-phenyl)-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-H-pyrrol-3-yl]-acrylamide-   27.    (E)-N-Hydroxy-3-[1-(4-morpholin-4-ylmethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   28.    (E)-N-Hydroxy-3-{1-[4-({(2-hydroxy-ethyl)-[2-(1H-indol-2-yl)-ethyl]-amino}methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide-   29.    (E)-N-Hydroxy-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   30.    (E)-N-(2-Amino-phenyl)-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   31.    (E)-N-(2-Amino-phenyl)-3-[1-(3-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide-   32.    (E)-N-Hydroxy-3-{1-[3-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}acrylamide    and-   33.    (E)-N-(2-Amino-phenyl)-3-{1-[3-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide,    and the salts thereof.

In a particular embodiment of aspect 3, the present invention providessalts of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidewith hydrochloric acid, particularly being in crystalline form, theirhydrates, as well as specific polymorphs and mixtures thereof.

In another particular embodiment of aspect 3, the present inventionrelates to(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidehydrochloride, particularly being in crystalline form, as well as tospecific polymorphs and mixtures thereof.

In another particular embodiment of aspect 3, the present inventionrelates to hydrochloride salts of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide,particularly being in crystalline form, hydrates and specific polymorphsthereof.

In another particular embodiment of aspect 3, the present inventionrelates to specific polymorphs of hydrochloride salts of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide,and hydrates thereof.

In another particular embodiment of aspect 3, the present inventionrelates to(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidemono-hydrochloride, particularly being in crystalline form, as well asto specific polymorphs and mixtures thereof.

In yet another particular embodiment of aspect 3, the present inventionrelates to(E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamidehydrochloride.

The compounds according to the present invention can be prepared, forexample, as shown in the reaction schemes below and according to thereaction steps specified as follows, or, particularly, in a manner asdescribed by way of example in the following examples, or analogously orsimilarly thereto using preparation procedures and synthesis strategiesknown to the person skilled in the art.

In reaction scheme 1 the carbon chain of compounds of formula V, inwhich R1, R2, R4 and R5 have the meanings mentioned above, islengthened, for example, by a condensation reaction (with a malonic acidderivative) or by a Wittig or Julia reaction or, particularly in thecase when R2 is hydrogen, by a Horner-Wadsworth-Emmons reaction (with aβ-(alkoxycarbonyl)-phosphonic acid dialkyl ester) to obtain compounds offormula IV, in which R1, R2, R3, R4 and R5 have the meanings mentionedabove and PG1 stands for a suitable temporary protective group for thecarboxyl group, for example tert-butyl or one of those art-knownprotective groups mentioned in “Protective Groups in Organic Synthesis”by T. Greene and P. Wuts (John Wiley & Sons, Inc. 1999, 3^(rd) Ed.) orin “Protecting Groups (Thieme Foundations Organic Chemistry Series NGroup” by P. Kocienski (Thieme Medical Publishers, 2000).

Compounds of formula V, in which R1, R2, R4 and R5 have the meaningsmentioned above, are known, or can be prepared according to art-knownprocedures, or can be obtained as described in the following examplesfor the case that R2 is hydrogen from compounds of formula VI.

Compounds of formula VI are known or are accessible in a known manner oras described in the following examples.

Compounds of formula IV, in which R1, R2, R3, R4 and R5 have themeanings mentioned above and PG1 stands for a said suitable protectivegroup, can be reacted with compounds of formula R6-SO₂—X, in which R6has the meanings mentioned above and X is a suitable leaving group, suchas e.g. chlorine, to give the corresponding compounds of formula III.

In the next reaction step, the protective group PG1 of compounds offormula III can be removed in a manner as described in the followingexamples or according to an art-known manner to afford compounds offormula II.

Compounds of formula R6-SO₂—X are known or can be prepared in a knownmanner.

Compounds of formula II, in which R1, R2, R3, R4, R5 and R6 have themeanings given above, can be coupled with compounds of formulaeH₂N—O-PG2, in which PG2 is a suitable oxygen protective group such ase.g. a suitable silyl or tetrahydropyran-2-yl protective group, or IIa,in which PG3 stands for a suitable nitrogen protective group such ase.g. the tert-butyloxycarbonyl protective group, by reaction with amidebond linking reagents optionally in the presence of coupling additivesknown to the person skilled in the art. Exemplary amide bond linkingreagents known to the person skilled in the art which may be mentionedare, for example, carbodiimides (e.g. dicyclohexylcarbodiimide or,preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride), azodicarboxylic acid derivatives (e.g. diethylazodicarboxylate), uronium salts [e.g.O-(benzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium tetrafluoroborate orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate]and N,N′-carbonyldiimidazole.

Alternatively, compounds of formula II can be activated prior to thecoupling reaction by forming an acid halide or acid anhydride optionallyin an in-situ procedure without isolating the acid halide or acidanhydride.

Compounds of formulae H₂N—O-PG2 or IIa are known or can be preparedaccording to art-known processes.

Removal of the protective groups PG2 or PG3 can be obtained in a mannerknown for the person skilled in the art or as described in the followingexamples to give compounds of formula I, in which R1, R2, R3, R4, R5, R6and R7 have the meanings mentioned above.

Compounds of formula I, in which T2 is 1-4C-alkylene, particularlymethylene, can be prepared as outlined in the following reaction schemes2 to 5, and specified below, or as described by way of example in thefollowing examples, or analogously or similarly thereto.

As shown in reaction scheme 2 compounds of formula VII, in which T2 is1-4C-alkylene, particularly methylene, and Y1 is a suitable leavinggroup, such as e.g. iodine, chlorine or, particularly, bromine, and PG4stands for a suitable temporary protective group for the carboxyl group,for example tert-butyl, can be reacted with compounds of formulaHN(R611)R612 to give in an art-known nucleophilic substitution reactioncorresponding amino compounds, which are deprotected by removal of PG4to give corresponding free acids of formula VIII, which can be coupledwith compounds of formulae H₂N—O-PG2 or IIa as described above to give,after removal of PG2 and PG3, corresponding compounds of formula Ia.

Alternatively, as shown in reaction scheme 3, compounds of formula VII,in which T2 is 1-4C-alkylene, particularly methylene, and Y1 is asuitable leaving group, such as e.g. iodine, chlorine or, particularly,bromine, and PG4 stands for a suitable temporary protective group forthe carboxyl group, for example tert-butyl, can be reacted with atemporarily protected amine (a primary or, particularly, a secondaryone), such as e.g. phthalimide, to give in an art-known nucleophilicsubstitution reaction corresponding amino compounds, which aredeprotected by removal of PG4 to give corresponding free acids offormula IX, which can be coupled with compounds of formulae H₂N—O-PG2 orIIa as described above to give corresponding compounds of formula X.

The amino moiety of compounds of formula X can be deprotected in anart-known manner to give corresponding compounds of formula XI, such ase.g. when the phthalimido protective group is used, this can be removedin a manner customary per se to the skilled person, e.g. with the aid ofhydrazine.

Compounds of formula XI can be deprotected to give correspondingcompounds of formula Ib.

Alternatively, as shown in reaction scheme 4, compounds of formula XIcan be reacted with compounds of formula R611-Y1 and/or R612-Y2, inwhich R611 and R612 have the meanings given above and are different fromhydrogen and Y1 and Y2 are suitable leaving groups such as e.g.chlorine, bromine, iodine or a sulfonate (e.g. triflate) leaving group,to give in an art-known nucleophilic substitution reaction correspondingcompounds of formula XII or XII′.

Compounds of formula XII or XII′ can be deprotected to givecorresponding compounds of formula Ic or Id, respectively.

Yet alternatively, as shown in reaction scheme 5, compounds of formulaXI can be reacted with aldehydes or ketones in an reductive aminationreaction, such as e.g. compounds of formula XI can be reacted withbenzaldehyde, or compounds of formulae 1-3C-alkyl-CHO or Har1-CHO, inwhich Har1 has the meanings given above, to give in an art-knownreductive amination reaction corresponding compounds of formula XIII.

Compounds of formula XIII can be deprotected to give correspondingcompounds of formula Ie.

Compounds of formula VII can be obtained according to the synthesisroute shown in reaction scheme 1 and described above.

The abovementioned compounds of formulae HN(R611)R612, R611-Y1, R612-Y2,1-3C-alkyl-CHO or Har1-CHO are known or can be obtained according toart-known procedures.

Compounds of formula I, in which R6 is Aa1 or Ah1, can be prepared asoutlined in the following reaction scheme 6, and specified below, or asdescribed by way of example in the following examples, or analogously orsimilarly thereto.

As shown in reaction scheme 6 compounds of formula XIV, in which Y3 is asuitable leaving group, such as e.g. iodine or bromine, and PG5 standsfor a suitable temporary protective group for the carboxyl group, forexample tert-butyl, can be reacted with boronic acids of formulaR′—B(OH)₂, in which R′ is the terminal aryl or heteroaryl moiety of theabovementioned Aa1 or Ha1 radicals, or the boronic acid esters (e.g. thepinacol esters) thereof, to give in an art-known Suzuki reaction thecorresponding CC-coupled compounds, which are deprotected by removal ofPG5 to give corresponding free acids of formula XV, which can be coupledwith compounds of formulae H₂N—O-PG2 or IIa as described above to give,after removal of PG2 and PG3, corresponding compounds of formula If.

Alternatively, as shown in reaction scheme 7 compounds of formula XIV,in which Y3 is a suitable leaving group, such as e.g. iodine or bromine,and PG5 stands for a suitable temporary protective group for thecarboxyl group, for example tert-butyl, can be deprotected by removal ofPG5, and the free carboxylic acid can be then coupled with compounds offormulae H₂N—O-PG2 or IIa as described above to give correspondingcompounds of formula XVI. Compounds of formula XVI are reacted withboronic acids of formula R′—B(OH)₂, in which R′ is the terminal aryl orheteroaryl moiety of the abovementioned Aa1 or Ha1 radicals, or theboronic acid esters (e.g. the pinacol esters) thereof, to give in anart-known Suzuki reaction the corresponding CC-coupled compounds, whichare deprotected by removal of PG2 or PG3 to give corresponding compoundsof formula If.

The Suzuki reaction can be carried out in a manner habitual per se tothe skilled person or as described in the following examples, oranalogously or similarly thereto.

Compounds of formula XIV can be obtained according to the synthesisroute shown in reaction scheme 1 and described above.

The abovementioned compounds of formula R′—B(OH)₂ are known or can beobtained according to art-known procedures.

The reactions mentioned above can be expediently carried out analogouslyto the methods known to the person skilled in the art or as described byway of example in the following examples.

It is moreover known to the person skilled in the art that if there area number of reactive centers on a starting or intermediate compound itmay be necessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in“Protective Groups in Organic Synthesis” by T. Greene and P. Wuts (JohnWiley & Sons, Inc. 1999, 3^(rd) Ed.) or in “Protecting Groups (ThiemeFoundations Organic Chemistry Series N Group” by P. Kocienski (ThiemeMedical Publishers, 2000).

The isolation and purification of the substances according to theinvention is carried out in a manner known per se, e.g. by distillingoff the solvent in vacuo and recrystallizing the resulting residue froma suitable solvent or subjecting it to one of the customary purificationmethods, such as, for example, column chromatography on suitable supportmaterial.

Optionally, compounds of formula I can be converted into their salts,or, optionally, salts of the compounds of formula I can be convertedinto the free compounds.

Salts are obtained by dissolving the free compound in a suitable solvent(e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutylketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, achlorinated hydrocarbon, such as methylene chloride or chloroform, or alow molecular weight aliphatic alcohol such as methanol, ethanol orisopropanol) which contains the desired acid or base, or to which thedesired acid or base is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted byalkalization or by acidification into the free compounds, which in turncan be converted into salts. In this way, pharmacologically intolerablesalts can be converted into pharmacologically tolerable salts.

The salts according to aspect 3 of this invention, such as e.g. salts of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamideor(E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,respectively, with hydrochloric acid, can be obtained as described byway of example herein, or analogously or similarly thereto.

As one possibility, salts can be prepared by methods known in the artfor making acid addition salts of amines, e.g. in the presence ofhydrochloric acid in a solution or suspension comprising a suitableorganic solvent (e.g. a lower alcohol, such as e.g. methanol, ethanol orisopropanol, a ketone, or an ether including dioxane, tetrahydrofurane,diethylether or tert-butyl methyl ether (TBME)), or mixture of organicsolvents, or mixtures thereof with water, or water, with or withoutheating. The salts are isolated by crystallization, filtering or byevaporation of the solvent(s) and, if desired, purified by washing orstirring with an appropriate solvent or mixture of solvents orrecrystallization from an appropriate recrystallization solvent ormixture of solvents by methods known to one of skill in the art.

Thus, depending on the reaction conditions used, the amount ofhydrochloric acid contained in the salts of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamideor(E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,respectively, with hydrochloric acid may lie in the range from about 0.1to about 1.9 equivalent, more precisely from about 0.3 to about 1.2equivalent, more precisely from about 0.6 to about 1.2 equivalent, moreprecisely from about 0.8 to about 1.2 equivalent, more precisely fromabout 0.9 to about 1.1 equivalent, more precisely about one, moreprecisely about 1.0 equivalent hydrochloric acid with respect to thefree base(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamideor(E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,respectively, determined according to art-known procedures, e.g.titration.

Crystalline hydrochloride salts of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidecan be obtained by a process comprising the step of crystallization orrecrystallization of any form or mixtures of any forms of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidewith hydrochloric acid in a solution comprising organic solvent (e.g. analcohol like methanol or ethanol, or a ketone like acetone) or mixtureof organic solvents, or mixtures thereof with water, or only water.

Polymorphs can be obtained by a number of methods, as known in the art.Such methods include, without being restricted to, solvent(re)crystallization, precipitating with non-solvent, rapid evaporation,slow evaporation, rapid cooling, slow cooling and the like.

The solvates or particularly hydrates of the compounds according to thisinvention can be prepared in a manner known per se, e.g. in the presenceof the appropriate solvent. Hydrates may be obtained from water or frommixtures of water with polar organic solvents (for example alcohols,e.g. methanol, ethanol or isopropanol, or ketones, e.g. acetone).

Suitably, the conversions mentioned in this invention can be carried outanalogously or similarly to methods which are familiar per se to theperson skilled in the art.

The person skilled in the art knows on the basis of his/her knowledgeand on the basis of those synthesis routes, which are shown anddescribed within the description of this invention, how to find otherpossible synthesis routes for according to this invention. All theseother possible synthesis routes are also part of this invention.

The present invention also relates to the intermediates (including theirsalts, stereoisomers and salts of the stereoisomers), methods andprocesses, which are disclosed herein and which are useful insynthesizing compounds according to this invention. Thus, the presentinvention also relates to processes disclosed herein for preparingcompounds according to this invention, which processes comprise one ormore steps of converting and/or reacting the mentioned intermediateswith the appropriate reaction partners under conditions as disclosedherein.

Having described the invention in detail, the scope of the presentinvention is not limited only to those described characteristics orembodiments. As will be apparent to persons skilled in the art,modifications, analogies, variations, derivations, homologisations andadaptations to the described invention can be made on the base ofart-known knowledge and/or, particularly, on the base of the disclosure(e.g. the explicite, implicite or inherent disclosure) of the presentinvention without departing from the spirit and scope of this inventionas defined by the scope of the appended claims.

The following examples serve to illustrate the invention further withoutrestricting it. Likewise, further compounds according to this invention,whose preparation is not explicitly described, can be prepared in ananalogous manner or in a manner familiar per se to the person skilled inthe art using customary process techniques.

Any or all of the compounds of formula I, which are mentioned as finalproducts in the following examples, as well as their salts are apreferred subject of the present invention.

In addition, any or all of the salts of compounds of formula I, whichare mentioned as final products in the following examples, theirhydrates as well as the polymorphs of these salts and hydrates are apreferred subject of the present invention.

In further addition, any or all of the polymorphs of the salts ofcompounds of formula I, which are mentioned as final products in thefollowing examples, as well as their hydrates and mixtures thereof are apreferred subject of the present invention.

In the examples, MS stands for mass spectrum, M for molecular ion, TSPfor Thermospray Ionization, ESI for Electrospray Ionization, EI forElectron Ionization, h for hours, min for minutes. Other abbreviationsused herein have the meanings customary per se to the person skilled inthe art.

EXAMPLES Final Products

1. (E)-N-Hydroxy-3-[(toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-acrylamide

0.231 g of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid(compound A1) are dissolved in 8 ml of dichloromethane at roomtemperature. Then 50 μl of N,N-dimethylformamide (DMF) are added, 0.275g of oxalic acid chloride dissolved in 2 ml of dichloromethane are addeddropwise and stirred for 1.5 hour. To the solution are added 0.439 g ofO-(trimethylsilyl)hydroxylamine and stirred for 15 minutes. Then 20 mlof aqueous hydrochloric acid (1 M strength) are added and extracted withethyl acetate. The combined organic phase is dried over sodium sulfate.Afterwards it is filtered and evaporated under vacuo. The crude productis purified by silica gel flash chromatography using a gradient ofdichloromethane and methanol from 98:2 to 6:4 to yield 0.050 g of thetitle compound as a white solid.

MS (TSP): 307.0 (MH⁺, 100%)

¹H-NMR (DMSO-d6): ¹H-NMR (DMSO-d6): 2.37 (s, 3H); 6.12 (d, J=15.9 Hz,1H); 6.54 (m, 1H); 7.25 (m, J=16.1 Hz, 2H); 7.42 (d, J=8.1 Hz, 2H); 7.79(m, 1H); 7.85 (d, J=8.2 Hz, 2H); 8.96 (bs, exchangeable, 1H); 10.61 (bs,exchangeable, 1H)

2. N-Hydroxy-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylamide

0.189 g of(E)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-N-(tetrahydropyran-2-yloxy)-acrylamide(compound A2) are dissolved in 50 ml of a methanol/water (3/2) solution.Then 0.102 g of the acidic ion exchange resin amberlyst IR15 are addedand the mixture is stirred for 91 hours at ambient temperature. Themixture is filtered. The filtrate is evaporated. The residue iscrystallized from methanol to give 0.144 g of the title compound aswhite crystals.

MS (TSP): 307.0 (MH⁺, 100%)

¹H-NMR (DMSO-d6): 5.00 (s, 2H); 6.11 (d, J=15.7 Hz, 1H); 6.50 (m, 1H);6.96 (m, 1H); 7.11 (m, 2H); 7.32 (m, J=17 Hz, 5H); 8.90 (s,exchangeable, 1H); 10.60 (s, exchangeable, 1H)

3. (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide

The method used for preparation of this compound is analogous to themethod described for compound 2. Starting materials:(E)-3-(1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl)-N-(tetrahydro-pyran-2-yloxy)-acrylamide(compound A3) (0.150 g), methanol/water 3/2 (50 ml), amberlyst IR15(0.300 g).

Reaction conditions: room temperature, 34 hours.

Yield: 0.041 g, pale grey crystals

MS (ESI): 381.1 (MH⁺ —CH₃NO₂, 100%)

¹H-NMR (DMSO-d6): 6.14 (d, J=15.8 Hz, 1H); 6.58 (m, 1H); 7.31 (d, J=15.7Hz, 1H); 7.43 (m, J=6.9 Hz, 4H); 7.70 (m, J=6.6 Hz, 3H); 7.91 (d, J=8.0Hz, 2H); 8.02 (d, J=8.1 Hz, 2H); 8.92 (s, exchangeable, 1H); 10.60 (s,exchangeable, 1H)

4.(E)-3-[1-(4-Dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide

The method used for preparation of this compound is analogous to themethod described for compound 2. Starting materials:(E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide(compound A4) (0.200 g), methanol/water 3/2 (50 ml), amberlyst IR15(0.402 g). Reaction conditions: room temperature, 34 hours.

Yield: 0.098 g, pale red crystals

MS (ESI): 336.0 (MH⁺, 100%)

¹H-NMR (DMSO-d6): 6.10 (m, J=16.5 Hz, 1H); 6.49 (m, 1H); 6.75 (d, J=9.2Hz, 2H); 7.24 (m, 2H); 7.64 (m, J₁=8.6 Hz, J_(2=17.7) Hz, 3H); 8.89 (bs,exchangeable, 1H), 10.59 (bs, exchangeable, 1H)

5.(E)-N-(2-Amino-phenyl)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide

0.116 g of(2-{(E)-3-[1-(toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamicacid tert-butyl ester (compound A5) are dissolved in 20 ml ofdichloromethane at ambient temperature. 2 ml of trifluoroacetic acid(TFA) are added and the solution is stirred for 93 hour. The solvent isevaporated to dryness and to the residue are added 25 ml of water. Thewater phase is extracted exhaustively with ethyl acetate. Afterwards thecombined organic phases are dried over sodium sulfate and filtered. Thefiltrate is evaporated under vacuo. Then the residue is crystallizedfrom methanol to give 0.050 g of the title compound as white crystals.

MS (ESI): 382.0 (MH⁺, 100%)

¹H-NMR (DMSO-d6): 2.38 (s, 3H); 4.48 (s, exchangeable, 2H); 6.55 (m,3H); 6.71 (m, 1H); 6.90 (m, 1H); 7.40 (m, J=8.1 Hz, 5H); 7.70 (m, 1H);7.89 (d, J=8.3 Hz, 2H); 9.20 (s, exchangeable, 1H)

6.(E)-N-(2-Amino-phenyl)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylamide

The method used for preparation of this compound is analogous to themethod described for compound 5 with the exception that the product ispurified by silica gel flash chromatography using a gradient ofdichloromethane/methanol from 99:1 to 95:5.

Starting materials:{2-[(E)-3-[1-(phenylmethanesulfonyl-1-H-pyrrol-3-yl)-allanoylamino]-phenyl}-carbamicacid tert-butyl ester (compound A6) (0.146 g), CH₂Cl₂ (20 ml), TFA (2ml). Reaction conditions: room temperature, 65 hours.

Yield: 0.037 g, white crystals

MS (ESI): 382.0 (MH⁺)

¹H-NMR (DMSO-d6): 4.90 (s, 2H); 5.01 (s, exchangeable, 1H); 6.58 (m,J=5.7 Hz, 3H); 6.74 (m, J=6.7 Hz, 2H); 6.90 (m, 1H); 7.01 (m, 1H); 7.11(m, J=5.6, 2H); 7.34 (m, J₁=5.7 Hz, J₂=6.7 Hz, 5H); 9.25 (s,exchangeable, 1H)

7.(E)-N-(2-Amino-phenyl)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide

The method used for preparation of this compound is analogous to themethod described for compound 5.

Starting materials:(2-{(E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-allanoylamino}phenyl)-carbamicacid tert-butyl ester (compound A7) (0.460 mmol), CH₂Cl₂ (50 ml), TFA (5ml). Reaction conditions: room temperature, 18 hours.

Yield: 0.061 g, white crystals

MS (ESI): 444.0 (MH⁺)

¹H-NMR (DMSO-d6): 4.90 (bs, exchangeable, 2H); 6.58 (m, J₂=51.4 Hz,J₂=7.5 Hz, 3H); 6.71 (m, J₁=1.4 Hz, J₂=6.6 Hz, 1H); 6.90 (m, J₁=1.4 Hz,J₂=6.6 Hz, 1H); 7.40 (m, J=7.5 Hz, J₂=7.7 Hz, 6H); 7.78 (m, J=7.7 Hz,3H); 7.95 (d, J=8.6 Hz, 2H); 8.08 (d, J=8.8 Hz, 2H); 9.23 (s,exchangeable, 1H)

8.(E)-N-(2-Amino-phenyl)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

The method used for preparation of this compound is analogous to themethod described for compound 5 with the exception that the product ispurified by crystallization from ethyl acetate.

Starting materials:(2-{(E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}phenyl)-carbamicacid tert-butyl ester (compound A8) (0.141 g), CH₂Cl₂ (10 ml), TFA (1ml). Reaction conditions: room temperature, 20 hours.

Yield: 0.109 g, pale red crystals

MS (ESI): 411.0 (MH⁺, 100%)

¹H-NMR (DMSO-d6): 3.00 (s, 6H); 3.97 (s, exchangeable, 2H); 6.79 (m,J=15.4 Hz, 2H); 6.79 (d, J=9.2 Hz, 2H); 7.04 (m, J₁=2.7 Hz, J₂=8.7 Hz,J₃=15.5 Hz, 3H); 7.40 (m, J₁=15.6 Hz, J₂=8.6 Hz, 3H) 7.70 (m, J₁=2.9 Hz,J₂=9.2 Hz, 3H) 9.74 (s, exchangeable, 1H)

9.(E)-N-Hydroxy-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-amino)-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylamide

81 mg of(E)-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-amino)-benzenesulfonyl]-1H-pyrrol-3-yl)-N-(tetrahydropyran-2-yloxy)-acrylamide(compound A9) are dissolved in 5 ml of methanol. After addition of 15 mlof 0.1N hydrochloric acid the mixture is stirred for 21 hour. Then thereaction mixture is evaporated. The residue is washed with ethyl acetateand dried under vacuum at −50° C.

Yield: 55 mg, pale yellow solid

10.(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide

Procedure a:

The method used for to preparation of this compound is analogous to themethod described for compound 9.

Starting material:(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-tetrahydro-pyran-2-yloxy)-acrylamide(compound A10)

Procedure b:

According to preferred procedure, the title compound can be obtained asfollows:

704 mg of the compound, which is obtained according to the procedure adescribed in Example 10, is suspended in 1.8 mL isopropanol and 1.8 mLwater. The suspension is heated to reflux until the residue isdissolved. 1.9 mL aqueous sodium hydroxide solution (1 mol/l) is addedand the solution is cooled to 5° C. The crystals are filtered by suctionand the residue is dried by vacuum. Off white crystals (601 mg) of(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamideare obtained.

1H-NMR (200 MHz, d6-DMSO): δ=2.13 (s, 6H, 2 CH₃), 3.46 (s, 2H, CH₂),6.15 (d, 1H, J=16.1 Hz, CH═CH), 6.57 (bs, 1H, Ar—H), 7.29 (d, 1H, J=16.1Hz, CH═CH), 7.37 (m, 1H, Ar—H), 7.56 (d, 2H, J=8.8 Hz, Ar—H), 7.69 (s,1H, Ar—H), 7.93 (d, 2H, J=8.8 Hz, Ar—H), 8.93 (bs, 1H, exchangeable-H),10.58 (bs, 1H, exchangeable-H)

11.(E)-N-Hydroxy-3-[1-(4-{[(pyridin-3-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A11, the method which can be used for thepreparation is analogous to the method described for compound 9. Thecrude product is pure enough for biological testing.

MH+=413.0

12.(E)-N-Hydroxy-3-[1-(4-{[(1H-indol-3-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A12, the method which can be used for thepreparation is analogous to the method described for compound 9. Thecrude product is pure enough for biological testing.

MH+=449.0

13.(E)-3-{1-[4-(Benzylamino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-hydroxy-acrylamide

Starting from compound A13, the method which can be used for thepreparation is analogous to the method described for compound 9.

MH+=412.1

14.(E)-N-Hydroxy-3-{1-[4]isobutylamino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide

Starting from compound A14, the method which can be used for thepreparation is analogous to the method described for compound 9.

MH+=378.1

15.(E)-N-Hydroxy-3-[1-(4-{[(1H-indol-5-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A15, the method which can be used for thepreparation is analogous to the method described for compound 9.

MH⁻=449.1

16.(E)-N-Hydroxy-3-[1-(4-{[(pyridin-4-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A16, the method which can be used for thepreparation is analogous to the method described for compound 9.

MH+=413.1

17.(E)-3-[1-(4-Aminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide

Starting from compound B6, the method which can be used for thepreparation is analogous to the method described for compound 9. Thecrude product is purified by washing with methanol. A solid is obtainedin 69% yield.

Melting point: 227.0-228.6° C.

18.(E)-N-Hydroxy-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A17, the method which can be used for thepreparation is analogous to the method described for compound 9. Thereaction mixture is partly evaporated and the resulting suspension isfiltered. The product is isolated as colorless solid.

Melting point: 219.3-221.4° C.

19.(E)-N-Hydroxy-3-{1-[441H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide

Starting from compound A18, the method which can be used for thepreparation is analogous to the method described for compound 9.

Melting point: 203.8-211.9° C.

20.(E)-N-(2-Amino-phenyl)-3-[1-(4-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A19, the method which can be used for thepreparation is analogous to the method described for compound 21.

Melting point: 244.2-246.5° C.

21.(E)-N-(2-Amino-phenyl)-3-[1-(4-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

The compound is prepared by treatment of(2-{(E)-3-[1-(4-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}phenyl)-carbamicacid tert-butyl ester (compound A20) in dioxane with HCl. After thereaction is finished, the product precipitates from the reactionmixture.

Melting point: 199.7-202.3° C.

22.(E)-N-(2-Amino-phenyl)-3-{1-[4-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide

Starting from compound A21, the method which can be used for thepreparation is analogous to the method described for compound 21.

Melting point: 232.3-240.9° C.

23. (E)-3-[1-(Biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide

Starting from compound A22, the method which can be used for thepreparation is analogous to the method described for compound 9.

Melting point: 114-159.4° C. Sinter at 83° C.

24.(E)-N-Hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A23, the method which can be used for thepreparation is analogous to the method described for compound 9. Theproduct crystallizes from the reaction mixture.

Melting point: 181.3-182° C.

25.(E)-N-Hydroxy-3-[1-(4-pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A24, the method which can be used for thepreparation is analogous to the method described for compound 9. Thecrude product is purified by washing with dichloromethane.

Melting point: 160.7-166.6° C.

26.(E)-N-(2-Amino-phenyl)-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A25, the method which can be used for thepreparation is analogous to the method described for compound 21. Theproduct is purified by washing the crude product with ethyl acetate.

Melting point: 171.3-174.7° C.

27.(E)-N-Hydroxy-3-[1-(4-morpholin-4-ylmethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide

Starting from compound A26, the method which can be used for thepreparation is analogous to the method described for compound 9. Thetitle compound is isolated by freeze-drying methods.

Melting point: 168-170° C.

28.(E)-N-Hydroxy-3-{1-[4-({(2-hydroxy-ethyl)-[2-(1H-indol-2-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide

Starting from compound A 27, the method which can be used for thepreparation is analogous to the method described for compound 9. Thereaction mixture is evaporated and the title compound is isolated as anoil.

MH+=509.1

Starting from compound D6, the following compounds may be prepared viasynthesis routes which are analogous to the synthesis routes resultingto the Examples 18 to 22.

29.(E)-N-Hydroxy-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide30.(E)-N-(2-Amino-phenyl)-3-[1-(3-pyridin-4-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide31.(E)-N-(2-Amino-phenyl)-3-[1-(3-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide32.(E)-N-Hydroxy-3-{1-[3-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamide33.(E)-N-(2-Amino-phenyl)-3-{1-[3-(1H-pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylamideSalts of(E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamidewith hydrochloric acid

(E)-N-Hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide;compound with about 0.3 equivalent hydrochloric acid with respect to thefree base:

200 mg of the compound, which is obtained according to the proceduredescribed in Example 24, is suspended in 7 ml 1 N HCl. 3 drops ofmethanol are added. The suspension is heated to 80° C. and stirred at RTfor 2.5 h. Afterwards the suspension is cooled in an ice-bath. The solidis filtered, washed with 20 ml water and dried overnight on high vacuum.Yellow crystals (200 mg) are obtained with a melting point of 172-175°C. The compound contains 0.30 eq HCl/mol and 5.0% wt water.

Salt of(E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamidewith hydrochloric acid

1000 mg(E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamideis suspended in 10 mL hydrochloric acid in isopropanol (5 mol/l) Thesuspension is stirred for 2 h at room temperature. The solvent isevaporated and the residue is suspended in 10 mL isopropanol. Afterstirring for 24 h the crystals are filtered and dried in vacuum. Beigecrystals (730 mg) are obtained. The compound contains 0.91 eqhydrochloric acid/mol.

1H-NMR (200 MHz, d6-DMSO): δ=6.19 (d, 1H, J=15.8 Hz, CH═CH), 6.61 (bs,1H, Ar—H), 7.25-7.47 (m, 3H, CH═CH, 2 Ar—H), 7.72 (bs, 1H, Ar—H),7.86-8.00 (m, 3H, 3 Ar—H), 8.08 (d, 1H, J=8.1 Hz, Ar—H), 8.58 (d, 1H,J=4.6 Hz, Ar—H)

Salts of(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidewith hydrochloric acid

Form A polymorph of a hydrochloride salt of(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide:

a.) Form A polymorph with about 1.0 equivalent hydrochloric acid withrespect to the free base:

200 mg of the compound, which is obtained according to the procedure adescribed in Example 10, is dissolved in aqueous hydrochloric acid (30ml, 1 M) with a drop of methanol by heating. Now it is cooled quickly bymeans of an ice bath. During the cooling procedure pale pink crystalsare formed. The product is filtrated and dried under vacuum.

Melting point: 215-219° C.

Content of HCl: 0.95 HCl/mol

Yield: 99 mg (pale pink crystals, cube form)

X-ray powder diffraction pattern: characteristic peaks of this compoundare substantially summarized in Table A and substantially shown in FIG.Aa given later in this application.

Alternatively:

b.) Form A polymorph with about 0.9 equivalent hydrochloric acid withrespect to the free base:

200 mg of the compound, which is obtained according to the procedure adescribed in Example 10, is dissolved in aqueous hydrochloric acid (30ml, 1M) with a drop of ethanol by heating. Now is added slowly isopropylether (15 ml). There are formed two phases. This mixture is evaporatedat 40° C. During the evaporation process there are formed slowlycrystals. Now the evaporation is stopped and the mixture is cooled toroom temperature. The product is filtrated and dried under vacuum.

Melting point: 216-217° C.; Content of HCl: 0.85 HCl/mol; Contains ca.4.4% wt water;

Yield: 139 mg (pale yellow crystals, plat form);

X-ray powder diffraction pattern: characteristic peaks of this compoundare substantially summarized in Table A and substantially shown in FIG.Ab given later in this application;

Differential Scanning Calorimetry: thermoanalytical properties of thiscompound are substantially summarized in Table C given later in thisapplication.

Form B polymorph of a hydrochloride salt of(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide:

a.) Form B polymorph with about 1.0 equivalent hydrochloric acid withrespect to the free base:

200 mg of the compound, which is obtained according to the procedure adescribed in Example 10, is dissolved in aqueous hydrochloric acid (30ml, 1 M) with a drop of methanol by heating. During cooling overnight toroom temperature pale pink crystals are formed. The crystals arefiltered and dried under vacuum. Melting point: 224-226° C.; Content ofHCl: 0.96 HCl/mol;

Yield: 137 mg (pale pink crystals, split form);

X-ray powder diffraction pattern: characteristic peaks of this compoundare substantially summarized in Table B and shown in FIG. B given laterin this application;

Differential Scanning Calorimetry: thermoanalytical properties of thiscompound are substantially summarized in Table D given later in thisapplication.

Further forms of salts of(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidewith hydrochloric acid:

Salt of(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidewith about 1.0 equivalent hydrochloric acid with respect to the freebase:

200 mg of the compound, which is obtained according to the procedure adescribed in Example 10, is dissolved in hydrochloric acid (20 ml, 1 N),acetone (5 ml) and methanol (1 ml) by heating. After cooling overnightthe solution was evaporated. During evaporation crystals are formed andthe evaporation process is stopped. The mixture is cooled overnight toambient temperature and the resulting crystals are collected by suctionand dried in vacuum. Melting point: 217-220° C.

Content of HCl: 1.02 HCl/mol; Contains 0.82% wt water;

Yield: 131 mg (pale grey white solids).

Salt of(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidewith about 0.3 equivalent hydrochloric acid with respect to the freebase:

2.04 g of the compound, which is obtained according to the procedure adescribed in Example 10, is dissolved in hydrochloric acid (1M) andmethanol (11, ration 1:1). Then the solution is neutralized with sodiumhydroxide solution (10N). This solution is lyophylized. The resultingsolid is suspended extensively in ca. 100 ml of water. The crystals arecollected by suction and dried in vacuum.

Melting point: 217-219° C.

Content of HCl: 0.33 HCl/mol; Contains 3.9% wt water;

Yield: 534 mg (white solid).

Salt of(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidewith about 0.7 equivalent hydrochloric acid with respect to the freebase:

200 mg of the compound, which is obtained according to the procedure adescribed in Example 10, is dissolved in hydrochloric acid (30 ml, 1 N)and a drop of ethanol by heating. During cooling to room temperatureovernight crystals are obtained. The crystals are collected and driedunder vacuum.

Melting point: 219-221° C.; Content of HCl: 0.74 HCl/mol;

Yield: 110 mg (pale pink crystals).

Unless otherwise noted, the aforementioned melting points are determinedby heating the solid products in small glass vessels under visualinspection. The heating rate is between 0.5 and 10° C./min in a Büchimelting point apparatus B-540.

Starting Materials

A1 (E)-3-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3yl]-acrylic acid

1.60 g of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester (compound C1) are dissolved in 70 ml of dichloromethaneat ambient temperature. Then 7 ml of trifluoroacetic acid (TFA) areadded and stirred for 4 hours. The solvent is evaporated to dryness andto the residue are added 30 ml of water. The water phase is extractedexhaustively with ethyl acetate. Then the organic phase is dried oversodium sulfate. The filtrate is evaporated and dried under vacuo to give0.951 g of the title compound as a pale grey solid.

MS (TSP): 290.0 (M-H⁺, 100%)

¹H-NMR (DMSO-d6): 2.36 (s, 3H); 6.20 (d, J=15.9 Hz, 1H); 6.74 (m, J=3.1Hz, 1H); 7.41 (m, J₁=3.1 Hz, J₂=8.2 Hz, J₃=16.1 Hz, 4H); 7.78 (m, 1H),7.87 (d, J=8.4 Hz, 2H); 11.80 (bs, exchangeable, 1H)

A2(E)-3-(1-Phenylmethanesulfonyl-1H-pyrrol-3-yl)-N-(tetrahydropyran-2-yloxy)-acrylamide

0.295 g of (E)-3-(1-phenylmethansulfonyl-1H-pyrrol-3-yl)-acrylic acid(compound B1), 0.152 g of N-hydroxybenzotriazole hydrate (HOBt.H₂O) and561 μl of triethylamine are dissolved in 20 ml of N,N-dimethylformamide

(DMF) at room temperature. Afterwards it is added 0.601 g ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl)and stirred for 1 hour at room temperature. Then is added 0.152 g ofO-(tetrahydro-2H-pyran-2-yl)-hydroxylamine and stirred for 2 hour. TheDMF is evaporated under high vacuo. Water is added and the mixture wasextracted with ethyl acetate. The organic phase is dried over sodiumsulfate. Then it is filtered and evaporated under vacuo. The crudeproduct is purified by silica gel flash chromatography using a gradientof dichloromethane/methanol from 99:1 to 98:2 to give 0.189 g of thetitle compound as a pale grey solid.

MS (ESI): 390.9 (MH⁺, 100%)

¹H-NMR (DMSO-d6): 1.60 (m, 6H); 3.51 (m, 1H); 3.91 (m, 1H); 4.89 (m,1H); 5.00 (s, 2H); 6.18 (d, J=15.3 Hz, 1H); 6.50 (s, 1H); 6.96 (m, J=5.2Hz, 1H); 7.10 (m, J₁=7.3 Hz, J₂=7.9 Hz, 2H); 7.30 (m, J₁=5.1 Hz, J₂=7.3Hz, J₃=8.1 Hz, J₄=8.1 Hz, J₅=15.2 Hz, 5H); 10.60 (s, exchangeable, 1H);11.08 (bs, exchangeable, 1H)

A3(E)-3-(1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl)-N-(tetrahydro-pyran-2-yloxy)-acrylamide

The method used for preparation of this compound is analogous to themethod described for compound A2 with the exception that the product ispurified by crystallization from water and methanol.

Starting materials:(E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compoundB2) (0.300 g), HOBt.H₂O (0.130 g), triethylamine (668 μl), DMF (20 ml),EDC.HCl (0.508 g), O-(tetrahydro-2H-pyran-yl)hydroxylamine (0.089 g).Reaction conditions: room temperature, 1 hour; room temperature, 18hours.

Yield: 0.345 g, pale grey solid

MS (ESI): 452.8 (MH⁺); 369.0 (MH⁺ —C₅H₉O, 100%)

¹H-NMR (DMSO-d6): 1.61 (m, 6); 3.50 (m, 1H); 3.92 (m, 1H); 4.87 (m, 1H);6.21 (d, J=14.7 Hz, 1H); 6.60 (s, 1H); 7.48 (m, J=6.9 Hz, 5H); 7.72 (m,J₁=7.0 Hz, J₂=14.7 Hz, 3H); 7.98 (d, J=8.5 Hz, 2H); 8.06 (d, J=8.6 Hz,2H); 11.06 (bs, exchangeable, 1H)

A4 (E)-3-[1-(4-Dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-Ntetrahydro-pyran-2-yloxy)-acrylamide

The method used for preparation of this compound is analogous to themethod described for compound A2 with the exception that the product ispurified by silica gel flash chromatography using a gradient ofdichloromethane and methanol from 99:1 to 98:2.

Starting materials:(E)-3-[1-(4-dimethylamino-benzensulfonyl)-1H-pyrrol-3-yl)-acrylic acid(compound B3) (0.150 g), HOBt.H₂O (0.072 g), triethylamine (259 μl), DMF(10 ml), EDC.HCl (0.269 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine(0.049 g). Reaction conditions: room temperature, 1 hour; roomtemperature, 17 hours.

Yield: 0.187 g, pale red solid

MS (ESI): 419.2 (MH⁺); 336.0 (MH⁺ —C₅H₉O, 100%)

¹H-NMR (DMSO-d6): 1.61 (m, 6); 3.02 (s, 6H); 3.50 (m, 1H); 3.92 (m, 1H);4.85 (m, 1H); 6.19 (m, 1H); 6.50 (m, 1H); 6.75 (m, J=9.2 Hz, 2H); 7.31(m, 2H); 7.64 (m, J=9.2 Hz, 3H); 11.01 (bs, exchangeable, 1H)

A5(2{(E)-3-[1-(Toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamicacid tert-butyl ester

The method used for preparation of this compound is analogous to themethod described for compound A2 with the exception that the product ispurified by silica gel flash chromatography using a gradient ofdichloromethane and methanol from 99:1 to 98:1.

Starting materials:(E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound A1)(0.400 g), HOBt.H₂O (0.285 g), triethylamine (652 μl), DMF (25 ml),EDC.HCl (0.698 g), N-BOC-1,2,-phenylenediamine (0.286 g). Reactionconditions: room temperature, 1 hour; room temperature, 2 hours.

Yield: 0.609 g, pale grey solid

MS (ESI): 481.7 (MH⁴, 100%)

¹H-NMR (DMSO-d6): 1.40 (m, 9H); 2.39 (s, 3H); 6.61 (m, J₁=1.7 Hz, J₂=2.2Hz, J₃=5.0 Hz, 2H); 7.09 (m, J₁=1.8 Hz, J₂=2.3 Hz, 2H); 7.37 (m, J₁=2.0Hz, J₂=5.0 Hz, J₃=8.0 Hz, 4H); 7.64 (m, 1H); 7.88 (d, J=8.4 Hz, 2H);8.41 (s, exchangeable, 1H); 9.57 (s, exchangeable, 1H)

A6{2-[(E)-3-[1-(Phenylmethanesulfonyl-1-H-pyrrol-3-yl)-allanoylamino]-phenyl}-carbamicacid tert-butyl ester

The method used for preparation of this compound is analogous to themethod described for compound A2 with the exception that the product ispurified by silica gel flash chromatography using a gradient ofdichloromethane and methanol from 99:1 to 95:5.

Starting materials:(E)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylic acid (compoundB1) (0.180 g), HOBt.H₂O (0.090 g), triethylamine (295 μl), DMF (10 ml),EDC.HCl (0.315 g), N-BOC-1,2,-phenylenediamine (0.081 g). Reactionconditions: room temperature, 1 hour; room temperature, 17 hours.

Yield: 0.218 g, pale grey solid

MS (ESI): 504.0 (MNa⁺, 100%); 481.8 (MH⁺)

¹H-NMR (DMSO-d6): 1.42 (m, 9H); 5.04 (s, 2H); 6.56 (m, J₁=2.2 Hz,J₂=10.2 Hz, 2H); 7.14 (m, J₁=2.2 Hz, J₂=5.5 Hz, J₃=10.1 Hz, 4H); 7.36(m, J=5.5 Hz, J₂=7.2 Hz, 4H); 7.52 (m, J=2.2 Hz, J₂=7.2 Hz, 2H); 8.49(s, exchangeable, 1H); 9.67 (s, exchangeable, 1H)

A7(2-{(E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamicacid tert-butyl ester

The method used for preparation of this compound is analogous to themethod described for compound A2 with the exception that the product ispurified by silica gel flash chromatography using a gradient oftoluene/ethyl acetate from 99:1 to 9:1.

Starting materials:(E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compoundB2) (0.300 g), HOBt.H₂O (0.130 g), triethylamine (668 μl), DMF (20 ml),EDC.HCl (0.508 g), N-BOC-1,2,-phenylenediamine (0.176 g). Reactionconditions: room temperature, 1 hour; room temperature, 17 hours.

Yield: 0.285 g, pale grey solid

MS (ESI): 543.8 (MH⁺); 487.9 (MH⁺ —C₄H₈); 336.1 (MH⁺ —C₁₁H₁₄N₂O₂, 100%)

¹H-NMR (DMSO-d6): 1.47 (m, 9H); 6.50 (m, J=5.4 Hz, 1H); 6.64 (m, J=7.7Hz, 2H); 7.10 (m, J₁=5.4 Hz, J₂=7.7 Hz, 3H); 7.51 (m, J₁=J₂=J₃=3.6 Hz,5H); 7.73 (m, 2H); 7.81 (m, 1H); 7.96 (d, J=8.6 Hz, 2H); 8.08 (d, J=8.6Hz, 2H); 8.41 (s, exchangeable, 1H); 8.59 (s, exchangeable, 1H)

A8(2-{(E)-3-[1-(4-Dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamicacid tert-butyl ester

The method used for preparation of this compound is analogous to themethod described for compound A2 with the exception that the product ispurified by crystallization from ethyl acetate.

Starting materials:(E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl)-acrylic acid(compound B3) (0.150 g), HOBt.H₂O (0.072 g), triethylamine (259 μl), DMF(10 ml), EDC.HCl (0.269 g), N-BOC-1,2-phenylenediamine (0.049 g).Reaction conditions: room temperature, 1 hour; room temperature, 21hours.

Yield: 0.142 g, pale red solid

MS (ESI): 510.9 (MH⁺, 100%)

¹H-NMR (DMSO-6): 1.42 (m, 9H); 3.00 (s, 6H); 6.51 (m, 2H) 6.79 (d, J=9.2Hz, 2H); 7.09 (m, J=5.5 Hz, 2H); 7.36 (m, 2H); 7.50 (m, J=5.5 Hz, 2H);7.70 (m, J=9.2 Hz, 2H); 8.41 (s, exchangeable, 1H); 9.55 (s,exchangeable, 1H)

A9(E)-3-(1-[4-(([2-(1H-Indol-2-yl)-ethyl]-methyl-amino)-benzenesulfonyl]-1H-pyrrol-3-yl)-N-(tetrahydropyran-2-yloxy)-acrylamide

825 mg of(E)-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-amino)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylicacid (compound B4), 165 mg of HOBt.H₂O and 1.24 ml of triethylamine aredissolved in 70 ml of DMF at room temperature. Afterwards it is added726 mg of EDC.HCl and stirred for 1 hour. Then 140 mg ofO-(tetrahydro-2H-pyran-2-yl)-hydroxylamine are added and stirred for 18hour. The DMF is evaporated under high vacuum. Then water is added tothe residue and extracted with ethyl acetate. The organic phase is driedover sodium sulfate and evaporated under vacuum. Then the mixture isevaporated and the crude product is purified by silica gel flashchromatography using a gradient of dichloromethane and methanol98:2-9:1.

Yield: 289 mg, pale red solid

A10(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3yl]-N-tetrahydro-pyran-2-yloxy)-acrylamide

The method used for to preparation of the title compound is analogous tothe method described for compound A9.

Starting materials:(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-yl]-acrylicacid (compound B5) (1.78 g), HOBt.H₂O (366 mg), triethylamine (2.1 ml),DMF (80 ml), EDC.HCl (1.54 g),O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (306 mg). Reaction condition:room temperature, 1 hour; room temperature, 48 hours.

Yield: 835 mg, pale yellow solid

A11(E)-3-[1-{(4-([(Pyridin-3-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide

A mixture of compound B6, sodium triacetoxyborohydride, methanol and3-pyridinecarboxaldehyde is stirred at ambient temperature overnight.The reaction mixture is evaporated and partitioned betweendichloromethane and water. The crude product is purified by silica gelflash chromatography. A nearly colorless oil is obtained.

Starting from compound B6 and the appropriate aldehyde the followingcompounds A12 to A16 can be obtained according to compound A1.

A12(E)-3-[1-(4-{[(1H-Indol-3-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamideA13(E)-3-{1-[4-(Benzylamino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamideA14(E)-3-{1-[4-(Isobutylamino-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamideA15(E)-3-[1-(4-{[(1H-Indol-5-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamideA16(E)-3-[1-(4-{[(Pyridin-4-ylmethyl)-amino]-methyl}-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamideA17 (E)-3-[1-(4-Pyridin-4-ylphenylsulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydropyran-2-yloxy)-acrylamide

Starting from compound B7 the title compound can be obtained accordingto compound A2.

A18(E)-3-{1-[4-(1H-Pyrazol-4-yl)-phenylsulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydropyran-2-yloxy)-acrylamide

Starting from compound B8 the title compound can be obtained accordingto compound A2.

A19[2-((E)-3-{1-[4-Pyridin-4-yl-benzenesulfonyl]-1H-pyrrol-3-yl}-allanoylamino)-phenyl]-carbamicacid tert-butyl ester

Starting from compound B7 the title compound can be obtained accordingto compound A5.

A20[2-((E)-3-{1-[4-Pyridin-3-yl-benzenesulfonyl]-1H-pyrrol-3-yl}-allanoylamino)-phenyl]-carbamicacid tert-butyl ester

Starting from compound B9 the title compound can be obtained accordingto compound A5.

A21[2-((E)-3-{1-[4-(1H-Pyrazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-allanoylamino)-phenyl]-carbamicacid tert-butyl ester

Starting from compound B8 the title compound can be obtained accordingto compound A5.

A22(E)-3-(1-(Biphenyl-3-sulfonyl)-1H-pyrrol-3-yl)-N-(tetrahydro-pyran-2-yloxy)-acrylamide

Starting from compound B10 the title compound can be obtained accordingto compound A2.

A23(E)-3-(1-(5-Pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl)-N-tetrahydro-pyran-2-yloxy)-acrylamide

Starting from compound B1 the title compound can be obtained accordingto compound A2.

A24(E)-3-(1-(4-Pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl)-N-(tetrahydro-pyran-2-yloxy)-acrylamide

Starting from compound B12 the title compound can be obtained accordingto compound A2.

A25(2-{(E)-3-[1-(5-Pyridin-2-yl-thiophene-2-yl-sulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamicacid tert-butyl ester

Starting from compound B1 the title compound can be obtained accordingto compound A5.

A26(E)-3-{1-[4-(Morpholin-4-yl-methyl)-benzenesulfonyl]-1H-pyrrol-3yl}-N-tetrahydro-pyran-2-yloxy)-acrylamide

Starting from compound B13 the title compound can be obtained accordingto compound A2.

A27(E)-3-{1-[4-({[2-hydroxy-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide

(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}N-(tetrahydro-pyran-2-yloxy)-acrylamide(compound B 14) (120 mg, 0.169 mmol) is dissolved in THF (20 ml). Thenit is added tetrabutylammonium fluoride (203 μl, 0.203, 1M in THF) andtriethylamine (47 μl, 0.338 mmol) and the mixture is stirred for 17hours. After addition of water (50 ml) and extraction with ethyl acetatethe organic phase is dried over sodium sulfate, filtrated andevaporated. The crude product is purified by a silica gel flashchromatography using dichloromethane-methanol eluent.

B1 (E)-3-(1-Phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylic acid

The method used for preparation of this compound is analogous to themethod described for compound A1 with the exception that the product isisolated by crystallization from a mixture of aceton (29.7 g), water(10.8 g) and HCl (C(HCl)=1 mol/l, 5.3 g).

Starting materials:(E)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylic acidtert-butylester

(compound C2) (1.45 g), CH₂Cl₂ (80 ml), TFA (8 ml). Reaction conditions:room temperature, 2 hours.

Yield: 0.660 g, pale grey crystals

MS (TSP): 289.9 (M-H⁺, 100%)

¹H-NMR (DMSO-d6): 5.00 (s, 2H); 6.21 (d, J=15.9 Hz, 1H); 6.72 (m, J₁=1.9Hz, J₂=3.4 Hz, 1H); 7.01 (m, J=5.3, 1H); 7.10 (m, J=1.6 Hz, 2H); 7.31(m, 7.41 (m, J₁=1.6 Hz, J₂=1.9 Hz, J₃=3.4 Hz, J₄=5.3 Hz, J₅=16.1 Hz, 4H)

B2 (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid

The method used for preparation of this compound is analogous to themethod described for compound A1.

Starting materials:(E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl)-acrylic acid tert-butylester (compound C3) (1.05 g), CH₂Cl₂ (100 ml), TFA (10 ml). Reactionconditions: room temperature, 21 hours.

Yield: 0.710 g, pale yellow solid

MS (ESI): 728.7 (2MNa⁺, 100%); 354.1 (MH⁺)

¹H-NMR (DMSO-d6): 6.29 (d, J=16.0 Hz, 1H); 6.81 (m, J₁=1.2 Hz, J₂=1.8Hz, J₃=3.0 Hz, 1H); 7.49 (m, J₁=3 Hz, J₂=7.7 Hz, J₀=16.0 Hz, 5H); 7.75(m, J₁=1.3 Hz, J₂=1.8 Hz, J₃=7.7 Hz, 2H); 7.85 (s, 1H); 7.95 (d, J=8.6Hz, 2H); 8.09 (d, J=8.6 Hz, 2H); 12.17 (bs, exchangeable, 1H)

B3 (E)-3-[1-(4-Dimethylamino-benzensulfonyl)-1H-pyrrol-3-yl)-acrylicacid

The method used for preparation of this compound is analogous to themethod described for compound A1.

Starting materials:(E)-3-[1-(4-dimethylamino-benzensulfonyl)-1H-pyrrol-3-yl)-acrylic acidtert-butyl ester (compound C4) (0.801 g), CH₂Cl₂ (100 ml), TFA (10 ml).Reaction conditions: room temperature, 16 hours.

Yield: 0.550 g, pale red solid

MS (ESI): 662.7 (2MNa⁺, 100%); 321.0 (MH⁺)

¹H-NMR (DMSO-d6): 2.98 (s, 6H); 6.16 (d, J=15.8 Hz, 1H); 6.68 (m, J=3.2Hz, 1H); 6.75 (m, J=9.2 Hz, 2H); 7.29 (m, J=2.9 Hz, 1H); 7.43 (d, J=15.9Hz, 1H); 7.70 (m, J=9.1 Hz, 3H); 12.11 (bs, exchangeable, 1H)

B4(E)-3-(1-[4-(([2-(1H-Indol-2-yl)-ethyl]-methyl-amino)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylicacid

1.01 g of(E)-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-amino)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylicacid tert-butyl ester (compound C5) are dissolved in 100 ml ofdichloromethane and stirred for 5 minutes. It is added 10 ml of TFA andthe mixture stirred for 19 hour. The solution is evaporated undervacuum. Then is added toluene to the residue (small amount to purify theTFA salt) and evaporated under vacuum.

Yield: 1.32 g, Pale brown solid

B5(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-yl]-acrylicacid

The method used for to preparation of this compound is analogous to themethod described for compound B4.

Starting materials:(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-yl]-acrylicacid tert-butyl ester (compound C6) (2.13 g), TFA (10 ml); 24 hour.

Yield: 3.21 g (with 3 TFA salt), pale brown solid

B6(E)-3-[1-(4-Aminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide

To a mixture of 1 g of compound C7 and 50 ml ethanol is added 0.57 mlhydrazine hydrate (80%). The mixture is refluxed for 2.5 h. Afterwards,the reaction mixture is cooled to ambient temperature and the resultingwhite suspension is filtered. The product in the filtrate is purified bysilica gel flash chromatography.

B7 (E)-3-[1-(4-Pyridin-4-ylphenylsulfonyl)-1H-pyrrol-3-yl]-acrylic acid

Starting from compound C8 the title compound can be obtained accordingto compound A1.

B8 (E)-3-{1-[4-(1H-Pyrazol-4-yl)-phenylsulfonyl]-1H-pyrrol-3-yl}-acrylicacid

Starting from compound C9 the title compound can be obtained accordingto compound A1.

B9 (E)-3-[1-(4-Pyridin-3-ylphenylsulfonyl)-1H-pyrrol-3-yl]-acrylic acid

Starting from compound C10 the title compound can be obtained accordingto compound A1.

B10 (E)-3-(1-(Biphenyl-3-sulfonyl)-1H-pyrrol-3-yl)-acrylic acid

Starting from compound C11 the title compound can be obtained accordingto compound A1.

B11(E)-3-(1-(5-Pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl)-acrylicacid

Starting from compound C12 the title compound can be obtained accordingto compound A1.

B12 (E)-3-(1-(4-Pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl)-acrylicacid

Starting from compound C13 the title compound can be obtained accordingto compound A1.

B13(E)-3-{1-[4-(Morpholin-4-yl-methyl)-benzenesulfonyl]-1H-pyrrol-3yl}-acrylicacid

Starting from compound C14 the title compound can be obtained accordingto compound A1.

B14(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide

(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}acrylicacid (compound C15) (1.15 g, 1.16 mmol), HOBt.H₂O (171 mg, 1.16 mmol)and triethylamine (2 ml) is dissolved in DMF (100 ml) at roomtemperature. After addition of EDC.HCl (786 mg, 3.48 mmol) the mixtureis stirred for 1.5 hours. Then it is addedO-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (136 mg, 1.16 mmol) andstirred for 17 hours. After evaporation and addition of 200 ml water themixture is extracted with ethyl acetate. The organic phase is dried oversodium sulfate. Then it is filtrated and evaporated. The crude productis purified by a silica gel flash chromatography usingdichloromethane-methanol eluent.

C1 (E)-3-[1-(Toluene-4-sulfonyl)-1H-pyrrol-3yl]-acrylic acid tert-butylester

0.230 g of sodium hydride (60%) is suspended in 6 ml of tetrahydrofuraneunder nitrogen at −30° C. 1.01 g of (E)-3-(1H-pyrrol-3-yl)acrylic acidtert-butyl ester (compound D1) are added to the suspension and warmedslowly to room temperature and stirred for 30 minutes. Afterwards it isrecooled to −30° C. and 1.19 g of p-toluenesulfonylchloride are addedand stirred for 2.5 hours. The suspension is warmed slowly at roomtemperature and 40 ml of saturated aqueous sodium chloride solution areadded. The mixture is extracted with ethyl acetate. The combined organicphase is dried over sodium sulfate (Na₂SO₄). Afterwards it is filteredand evaporated under vacuo. The crude product is purified by silica gelflash chromatography using a gradient of hexane-ethyl acetate from 9:1to 1:1 to give 1.60 g of the title compound as a pale yellow solid.

MS (ESI): 347.6 (MH⁺); 291.9 (MH⁺—C₄H₉, 100%)

¹H-NMR (DMSO-d6): 1.43 (s, 9H); 2.37 (s, 3H); 6.21 (d, J=15.9 Hz, 1H);6.74 (m, J=3.1 Hz, 1H); 7.40 (m, J₁=15.9 Hz, J₂=12.7 Hz, J₃=3.2 Hz, 4H);7.82 (m, J=12.6 Hz, 3H)

C2 (E)-3-(1-Phenylmethansulfonyl-1H-pyrrol-3-yl)-acrylic acidtert-butylester

The method used for preparation of this compound is analogous to themethod described for compound C1 with the exception that the product ispurified by silica gel flash chromatography using gradient ofhexane/ethyl acetate from 8:1 to 5:1.

Starting materials: sodium hydride 60% (0.240 g),(E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) (1.01g), α-toluenesulfonylchloride (1.19 g). Reaction conditions: −30° C., 30min; −30° C., 2.5 hours.

Yield: 1.45 g, pale yellow solid

MS (TSP): 346.3 (M-H⁺, 100%)

¹H-NMR (DMSO-d6): 1.47 (s, 9H); 5.00 (s, 2H); 6.21 (d, J=15.8 Hz, 1H);6.72 (m, J₁=1.8 Hz, J₂=3.3 Hz, 1H); 6.98 (m, J=5.3, 1H); 7.09 (m, J₁=2.1Hz, J₂=7.8 Hz, 2H); 7.31 (m, J₁=1.9 Hz, J₂=3.5 Hz, J₃=5.4 Hz, J₄=7.7 Hz,J₅=15.7 Hz, 5H)

C3 (E)-3-[1-(Biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester

The method used for preparation of this compound is analogous to themethod described for compound C1 with the exception that the product ispurified by silica gel flash chromatography using a gradient ofpetroleum ether/diethylether from 7:1 to 1:1.

Starting materials: sodium hydride 60% (0.207 g),(E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester

(compound D1) (0.531 g), 4-biphenylsulphonylchloride (0.834 g). Reactionconditions: −30° C., 10 min; −30° C., 30 min.

Yield: 1.05 g, pale yellow solid

MS (ESI): 354.0 (MH⁺ —C₄H₉, 100%)

¹H-NMR (DMSO-d6): 1.45 (s, 9H); 6.26 (d, J=15.9 Hz, 1H); 6.80 (m, J=1.7Hz, 1H); 7.47 (m, J=15.7 Hz, 5H); 7.72 (m, J=1.8 Hz, 2H); 7.87 (m, 1H),7.92 (d, J=8.7 Hz, 2H); 8.09 (d, J=8.6 Hz, 2H)

C4 (E)-3-[1-(4-Dimethylamino-benzensulfonyl)-1H-pyrrol-3-yl]-acrylicacid tert-butyl ester

The method used for preparation of this compound is analogous to themethod described for compound C1 with the exception that the product ispurified by silica gel flash chromatography using a gradient ofpetroleum ether/diethylether from 7:1 to 1:1.

Starting materials: sodium hydride 60% (0.031 g),(E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1)(0.100 g), 4-dimethylamino-benzenesulfonyl chloride (0.145 g). Reactionconditions: −30° C., 45 min; −30° C., 2.5 hours.

Yield: 0.160 g, pale red solid

MS (ESI): 376.8 (MH⁺); 321.0 (MH⁺ —C₄H₉, 100%)

¹H-NMR (DMSO-d6): 1.42 (s, 9H); 3.00 (s, 6H); 6.19 (d, J=15.8 Hz, 1H);6.72 (m, J=9.2 Hz, 3H); 7.25 (m, 1H); 7.37 (d, J=15.8 Hz, 1H); 7.69 (m,J=9.1 Hz, 3H)

C5(E)-3-(1-[4-(([2-(1H-Indol-2-yl)-ethyl]-methyl-amino)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylicacid tert-butyl ester

1.50 g of(E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester (compound D2) are dissolved in 70 ml of ethanol at roomtemperature. After addition of 0.486 ml of triethylamine and 696 mg ofomega-methyltryptamine it is stirred for 21 hour. Then the solution isevaporated under vacuum. The crude product is purified by silica gelflash chromatography using a gradient of hexane and ethyl acetate from5:1-2:1.

Yield: 1.08 g, pale yellow solid

C6(E)-3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-yl]-acrylicacid tert-butyl ester

The method used for to preparation of this compound is analogous to themethod described for compound C5 with the exception that the product wascrystallized in ethanol.

Starting materials:(E)-3-[1-(4-Bromomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester (compound D2) (3.94 g), ethanol (150 ml), dimethylamine(1.89 g)

Yield: 2.19 g, pale yellow solid

C7(E)-3-{1-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylicacid

Starting from compound D3 the method which can be used for thispreparation is analogous to the method described for the compound B4.The title compound is purified by washing with toluene.

Starting from (E)-3-[1-(4-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylicacid tert-butyl ester (compound D4) and the appropriate boronic acidderivative the following compounds C8 and C9 can be obtained accordingto compound C10.

C8 (E)-3-[1-(4-Pyridin-4-ylphenylsulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl esterC9 (E)-3-{1-[4-(1H-Pyrazol-4-yl)-phenylsulfonyl]-1H-pyrrol-3-yl}-acrylicacid tert-butyl esterC10 (E)-3-[1-(4-Pyridin-3-ylphenylsulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester

0.18 g (E)-3-[1-(4-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester (compound D4) and 62 mg 3-pyridylboronic acid aredissolved in 10 ml DME. A catalytic amount ofbis-(triphenylphosphin-palladium (II)-chloride and 0.6 ml of an aqueoussolution of sodium carbonate are added and the mixture is heated toreflux temperature overnight. The title compound is isolated by means ofchromatography.

C11 (E)-3-[1-(Biphenyl-3-sulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester

Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester(compound D1) and art-known 3-biphenylsulphonylchloride the titlecompound can be obtained analogously or similarly as described forcompound C1.

C12(E)-3-[1-(5-Pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylicacid tert-butyl ester

Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester(compound D1) and art-known 5-pyridin-2-yl-thiophene-2-sulfonylchloridethe title compound can be obtained analogously or similarly as describedfor compound C1.

C13 (E)-3-[1-(4-Pyrazol-1-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylicacid tert-butyl ester

Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester(compound D1) and art-known 4-pyrazol-1-yl-benzenesulfonylchloride thetitle compound can be obtained analogously or similarly as described forcompound C1.

C14(E)-3-{[4-(Morpholin-4-yl-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylicacid tert-butyl ester

Starting from compound D2 and morpholine the title compound can beobtained analogously as described for compound C5.

C15(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylicacid

(E)-3-{3-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylicacid tert-butyl ester (compound D5) is dissolved in dichloromethane (50ml). Then it is added TFA and the mixture is stirred for 26 hours. Afterevaporation, the residue is washed with toluene.

D1 (E)-3-(1H-Pyrrol-3-yl)-acrylic acid tert-butyl ester

5.29 g of sodium hydride 60% is suspended in 100 ml of tetrahydrofuraneunder nitrogen at −30° C. 27.81 g of tert-butyl diphosphono acetate areadded to the suspension and warmed slowly to room temperature andstirred for 30 minutes. Afterwards the mixture is recooled at −30° C.and it is added 5.24 g of 1H-pyrrol-3-carbaldehyde (compound E1) andstirred at −30° C. for 30 minutes. The suspension is warmed slowly toroom temperature and 200 ml of aqueous ammonia solution are added. Thenit is extracted with ethyl acetate. The combined organic phase is driedover Na₂SO₄, filtered and evaporated under vacuo. The crude product ispurified by silica gel flash chromatography using a gradient ofn-hexane-ethyl acetate from 2:1 to 1:1 to give 9.68 g of the titlecompound as a pale yellow solid.

MS (EI): 193.1 (M⁺); 137.1 (M⁺ —C₄H₈, 100%)

¹H-NMR (DMSO-d6): 1.45 (s, 9H); 5.96 (d, J=15.7 Hz, 1H); 6.40 (m, 1H);6.78 (m, 1H); 7.19 (m, 1H): 7.47 (d, J=15.7 Hz, 1H); 11.11 (bs,exchangeable, 1H)

D2 (E)-3-[1-(4-Bromomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester

4.25 g of sodium hydride (60% strength) are suspended in 300 ml of THFunder nitrogen at −30° C. 9.78 g of (E)-3-(1H-pyrrol-3-yl)-acrylic acidtert-butyl ester (compound D1) are added to the suspension and warmedslowly to room temperature during 55 min. Afterwards it is recooled to−30° C. and it is added 13.98 g of4-(bromomethyl)-benzenesulphonylchloride and stirred for 45 min. Then itis warmed to room temperature and stirred for 2 hour. After cooling to0-5° C. water is added. Then the mixture is extracted with ethyl acetateand the organic phase is dried over sodium sulfate. The organic phase isevaporated under vacuum. The crude product is purified by silica gelflash chromatography using a gradient of hexane and ethyl acetate from9:1-7:1.

Yield: 17.21 g, pale yellow solid

D3(E)-3-{1-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylicacid tert-butyl ester

10 g (E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylicacid tert-butyl ester (compound D2) is dissolved in acetone and 6.5 gpotassium phthalimide is added and the mixture is stirred for 17.5 h.The suspension is filtered and the product is purified bycrystallization.

D4 (E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester

Starting from compound D1 and 4-bromo-benzenesulfonyl chloride the titlecompound can be obtained analogously as described for compound D2.

D5(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylicacid tert-butyl ester

[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amine(compound E2) (830 mg, 2.60 mmol) is dissolved in ethanol (200 ml).(E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester (compound D4) (1.01 g, 2.37 mmol) is added and themixture is stirred for 43 hours and evaporated. The residue is purifiedby a silica gel flash chromatograph using petrol ether-ether eluent.

D6 (E)-3-[1-(3-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acidtert-butyl ester

Starting from compound D1 and 3-bromo-benzenesulfonyl chloride the titlecompound can be obtained analogously as described for compound D4.

E1 1H-Pyrrol-3-carbaldehyde

4.70 g of dimethyl-(1H-pyrrol-3-ylmethylene)-ammonium chlorid (compoundF1) are dissolved in 500 ml of 5.0% aqueous sodium hydroxide solutionand stirred for 4 hours at ambient temperature.

Afterwards the reaction mixture is extracted exhaustively with CH₂Cl₂.The combined organic phase is dried over Na₂SO₄. Then it is filtered andevaporated under vacuo. The crude product is purified by a silica gelflash chromatography using petroleum ether/diethylether 1:1 eluent toyield 3.01 g of the title compound as a pale yellow solid.

MS (EI): 95.1 (M⁺, 100%)

¹H-NMR (DMSO-d6): 6.42 (dd, J₁=1.5 Hz, J₂=6.5 Hz, 1H); 6.90 (m, 1H),7.69 (dd, J₁=1.5 Hz, J₂=6.4 Hz, 1H); 9.68 (s, 1H); 11.59 (bs,exchangeable, 1H)

E2[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3yl)-ethyl]-amine

Tryptamine (3.34 g, 20.85 mmol) and t-butyldimethylsilyloxylacetaldehyde(2.44 g, 13.99 mmol) is dissolved in dichloromethane (200 ml) for 10minutes. The mixture is cooled to 0° C. and it is added sodiumtriacetoxyborohydride (5.38 g, 25.38 mmol). The mixture is warmed slowlyto room temperature and stirred for 18 hours. Then water is added andthe mixture is extracted with dichloromethane. The organic phase isdried over sodium sulfate, filtered and evaporated. The crude product ispurified by a silica gel flash chromatograph usingdichloromethane-methanol eluent.

F1 Dimethyl-(1H-pyrrol-3-ylmethylene)-ammonium chlorid

10.60 g of (chloromethylene)dimethylammonium chloride and 6.25 g ofN-(triisopropylsilyl)-pyrrole are suspended in 200 ml of CH₂Cl₂ undernitrogen at 0-5° C. The suspension is warmed to 60° C. and stirred for30 minutes. Afterwards the mixture is cooled to ambient temperature. Thesuspension is filtered and washed with diethylether to give 5.67 g ofthe title compound as grey solid.

MS (ESI): 123.3 (MH⁺, 100%)

¹H-NMR (DMSO-d6): 3.55 (s, 3H); 3.63 (s, 3H); 6.82 (m, J₁=1.4 Hz, J₂=1.5Hz, J₃=J₄=4.8 Hz, 1H); 7.22 (dd, J₁=4.7 Hz, J₂=4.9, 1H), 8.00 (dd,J₁=1.6 Hz, J₂=1.7 Hz, 1H); 8.78 (s, 1H); 12.94 (bs, exchangeable, 1H)

X-Ray Powder Diffraction (XRPD):

The XRPD (X-ray powder diffraction) measurements given herein areperfomed in transmission, Cu-Kalpha, U=40 kV, I=30 mA

TABLE A XRPD pattern of polymorph A comprising the following peaks(relative intensities >10) 2Theta I (rel) 5.8 15.1 11.5 11.8 15.0 100.017.1 49.2 17.4 21.0 17.5 12.0 18.2 10.6 19.9 15.9 20.1 33.9 20.6 27.421.3 24.1 21.5 34.4 23.2 14.0 24.1 42.9 25.0 18.6 25.4 42.9 25.8 10.926.9 12.3 27.5 25.6 28.5 24.3 29.1 48.1 30.1 11.1 30.2 10.2 30.8 11.532.3 13.9

TABLE B XRPD pattern of polymorph B comprising the following peaks(relative intensities >10) 2Theta I (rel) 10.1 11.5 17.0 100.0 17.7 57.717.9 61.0 20.3 20.0 20.8 18.6 21.1 47.7 22.7 28.4 23.1 24.5 24.1 11.126.2 14.8 26.8 14.2 27.9 14.4 28.4 17.9 28.9 33.9 34.5 12.6

Differential Scanning Calorimetry (DSC):

The DSC scans of the investigated batches are carried out in atemperature range between 30-280° C. on a dynamical differentialscanning calorimeter of TA instruments (DSC Q1000, acquisition software:Q Series Explore Advantage for Q-Series Version 2.1.0.240 ThermalAdvantage release 4.1.0, analysis software: Universal Analysis 2000 forWindows 2000/XP v. 4.0C) with dry nitrogen as purge gas (50 mL/min) anda heating rate of 10 K/min. Before performing the DSC sample scans, aT4P calibration (baseline, cell constant, onset slope, cp constant,indium melting point temperature calibration) is carried out.

For the DSC measurements sample amounts between 1.5 and 2.5 mg areaccurately weighed into a standard aluminium DSC pan without pin hole(TA instruments, Part 900779.901, T11128) and non-hermetically sealed.

TABLE C Polymorph A with about 0.9 eq HCl Onset-Point/ Signal-Maximum/Enthalpy/ ° C. ° C. J/g Peak 1 Peak 2 Peak 1 Peak 2 Peak 1 Peak 2 153.0± 215.8 ± 153.3 ± 221.3 ± 62.7 ± −355.5 ± 0.3 0.7 0.2 0.2 7.1 9.4

TABLE D Polymorph B Onset-Point/ Signal-Maximum/ Enthalpy/ ° C. ° C. J/gPeak 1 Peak 2 Peak 1 Peak 2 Peak 1 Peak 2 — 225.9 ± 0.3 — 229.9 ± 0.3 —−364.8 ± 4.5

Commercial Utility

The compounds according to this invention have valuable pharmacologicalproperties by inhibiting histone deacetylase activity and function.,

Histone deacetylase (HDAC) means an enzyme with an activity towards theε-acetyl group of lysine residues within a substrate protein. HDACsubstrates are histone H2A, H2B, H3 or H4 proteins and isoforms butsubstrate proteins different to histones like, but not limited to, heatshock protein 90 (Hsp90), tubulin or the tumor suppressor protein p53exist. In particular histone deacetylases catalyse the hydrolysis theε-acetyl group of lysine residues within these substrate proteins,forming the free amino group of lysine.

Inhibition of histone deacetylase by compounds according to thisinvention means inhibiting the activity and function of one or more HDACisoenzymes, in particular isoenzymes selected from the so far knownhistone deacetylases, namely HDAC 1, 2, 3 and 8 (class I) and HDAC 4, 5,6, 7, 10 (class II), HDAC 11 as well as the NAD+ dependent class III(Sir2 homologues). In some preferred embodiment this inhibition is atleast about 50%, more preferable at least 75% and still more preferableabove 90%. Preferably, this inhibition is specific to a specific histonedeacetylase class (eg HDAC class I enzymes), a selection of isoenzymesof highest pathophysiological relevance (eg HDAC1, 2, 3 enzymes) or asingle isoenzyme (eg the HDAC 1 enzyme). The term histone deacetylaseinhibitor is used to identify a compound capable of interacting with ahistone deacetylase and inhibiting its activity, in particular itsenzymatic activity. In this context “head group” defines the residueswithin an histone deacetylase inhibitor responsible for interacting withthe active site of the enzyme, eg the Zn²⁺ ion.

The inhibition of histone deacetylases is determined in biochemicalassays of various formats and sources of enzymatic activity. HDACactivity is used either derived from nuclear or cellular extracts or byheterologous expression of a defined HDAC isoenzymes in E. coli, insectcells or mammalian cells. Since HDAC isoenzymes are active inmultiprotein complexes and form homo- and heterodimeres, nuclearextracts derived from human cancer cells, for example the human cervicalcarcinoma cell line HeLa, are preferred. These nuclear extracts containclass I and class II enzymes, but are enriched in class 1 enzymes. Forexpression of recombinant HDAC isoenzymes, mammalian expression systemslike HEK293 cells are preferred. The HDAC isoenzyme is expressed as afusion protein with an affinity tag, like the FLAG epitope. By affinitychromatography, the tagged protein is purified alone or in complex withendogenous proteins (eg other HDAC isoenzymes and coactivators/platformproteins). The biochemical assays are well described and well known topersons skilled in the art. As substrates, histone proteins, peptidesderived from histone proteins or other HDAC substrates as well asacetylated lysine mimetics are used. One preferred promiscuous HDACsubstrate is the tripeptide Ac—NH-GGK(Ac), coupled with the fluorophore7-aminomethylcoumarin (AMC).

The invention further relates to the use of the compounds according tothis invention for inhibiting histone deacetylase activity in cells andtissues, causing hyperacetylation of substrate proteins and asfunctional consequence for example the induction or repression of geneexpression, induction of protein degration, cell cycle arrest, inductionof differentiation and/or induction of apoptosis.

Cellular activity of a histone deacetylase inhibitor means any cellulareffect related to histone deacetylase inhibition, in particular proteinhyperacetylation, transcriptional repression and activation, inductionof apoptosis, differentiation and/or cytotoxicity.

The term “induction of apoptosis” and analogous terms are used toidentify a compound which executes programmed cell death in cellscontacted with that compound. Apoptosis is defined by complexbiochemical events within the contacted cell, such as the activation ofcystein specific proteinases (“caspases”) and the fragmentation ofchromatin. Induction of apoptosis in cells contacted with the compoundmight not necessarily coupled with inhibition of cell proliferation orcell differentiation. Preferably, the inhibition of proliferation,induction of differentiation and/or induction of apoptosis is specificto cells with aberrant cell growth.

“Cytotoxicity” in general means arresting proliferation and/or inducingapoptotic cell death in vitro in mammalian cells, in particular humancancer cells.

“Induction of differentiation” is defined as a process of cellularreprogramming leading to a reversible or irreversible cell cycle arrestin G0 and re-expression of a subset of genes typical for a certainspecialized normal cell type or tissue (eg re-expression of milk fatproteins and fat in mammary carcinoma cells).

Assays for quantification of cell proliferation, apoptosis ordifferentiation are well known to experts and state of the art. Forexample, metabolic activity which is linked to cellular proliferation isquantified using the Alamar Blue/Resazurin assay (O'Brian et al. Eur jBiochem 267, 5421-5426, 2000) and induction of apoptosis is quantifiedby measurement of chromatin fragmentation with the cell death detectionELISA commercialized by Roche. Examples for cellular assays for thedetermination of hyperacetylation of HDAC substrates are given bymeasuring core histone acetylation using specific antibodies by Westernblotting, reporter gene assays using respective responsive promoters orpromoter elements (eg the p21 promotor or the sp1 site as responsiveelement) or finally by image analysis again using acetylation specificantibodies for core histone proteins.

Compounds according to this invention can be commercially applicable dueto their HDAC inhibitory, anti-proliferative and/or apoptosis inducingactivity, which may be beneficial in the therapy of diseases responsivethereto, such as e.g. any of those diseases mentioned herein.

The invention further relates to a method for inhibiting, treating,ameliorating or preventing cellular neoplasia by administration of aneffective amount of a compound according to this invention to a mammal,in particular a human in need of such treatment. A “neoplasia” isdefined by cells displaying aberrant cell proliferation and/or survivaland/or a block in differentiation. The term neoplasia includes “benignneoplasia” which is described by hyperproliferation of cells, incapableof forming an aggressive, metastasizing tumor in-vivo, and, in contrast,“malignant neoplasia” which is described by cells with multiple cellularand biochemical abnormalities, capable of forming a systemic disease,for example forming tumor metastasis in distant organs.

The compounds according to the present invention are preferably used forthe treatment of malignant neoplasia, also described as cancer,characterized by tumor cells finally metastasizing into distinct organsor tissues. Examples of malignant neoplasia treated with theN-sulphonylpyrrole derivatives of the present invention include solidand hematological tumors. Solid tumors are exemplified by tumors of thebreast, bladder, bone, brain, central and peripheral nervous system,colon, endocrine glands (e.g. thyroid and adrenal cortex), esophagus,endometrium, germ cells, head and neck, kidney, liver, lung, larynx andhypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal,small intestine, soft tissue, testis, stomach, skin, ureter, vagina andvulva. Malignant neoplasia include inherited cancers exemplified byRetinoblastoma and Wilms tumor. In addition, malignant neoplasia includeprimary tumors in said organs and corresponding secondary tumors indistant organs (“tumor metastases”). Hematological tumors areexemplified by aggressive and indolent forms of leukemia and lymphoma,namely non-Hodgkins disease, chronic and acute myeloid leukemia(CML/AML), acute lymphoblastic leukemia (ALL), Hodgkins disease,multiple myeloma and T-cell lymphoma. Also included are myelodysplasticsyndrome, plasma cell neoplasia, paraneoplastic syndromes, cancers ofunknown primary site as well as AIDS related malignancies.

It is to be noted that a cancer disease as well as a malignant neoplasiadoes not necessarily require the formation of metastases in distantorgans. Certain tumors exert devastating effects on the primary organitself through their aggressive growth properties. These can lead to thedestruction of the tissue and organ structure finally resulting infailure of the assigned organ function.

Neoplastic cell proliferation might also effect normal cell behaviourand organ function. For example the formation of new blood vessels, aprocess described as neovascularization, is induced by tumors or tumormetastases. Compounds according to the invention can be commerciallyapplicable for treatment of pathophysiological relevant processes causedby benign or neoplastic cell proliferation, such as but not limited toneovascularization by unphysiological proliferation of vascularendothelial cells.

Drug resistance is of particular importance for the frequent failure ofstandard cancer therapeutics. This drug resistance is caused by variouscellular and molecular mechanisms like overexpression of drug effluxpumps, mutation within the cellular target protein or fusion proteinsformed by chromosomal translocations. The commercial applicability ofcompounds according to the present invention is not limited to 1^(st)line treatment of patients. Patients with resistance to cancerchemotherapeutics or target specific anti-cancer drugs can be alsoamenable for treatment with these compounds for e.g. 2^(nd) or 3^(rd)line treatment cycles. A prominent example is given by acutepromyelocytic leukemia patients with the PML-RARα fusion protein,resistant to standard therapy with retinoids. These patients can beresensitized towards retinoids by treatment with HDAC inhibitory drugslike the compounds according to the, present invention.

The invention further provides to a method for treating a mammal, inparticular a human, bearing a disease different to cellular neoplasia,sensitive to histone deacetylase inhibitor therapy comprisingadministering to said mammal a pharmacologically active andtherapeutically effective and tolerable amount of a compound accordingto this invention. These non malignant diseases include

(i) arthropathies and osteopathological conditions or diseases such asrheumatoid arthritis, osteoarthritis, gout, polyarthritis, and psoriaticarthritis,(ii) autoimmune diseases like systemic lupus erythematosus andtransplant rejection,(iii) hyperproliferative diseases such as smooth muscle cellproliferation including vascular proliferative disorders,atherosclerosis and restenosis(iv) acute and chronic inflammatory conditions or diseases and dermalconditions such as ulcerative colitis, Chrons disease, allergicrhinitis, allergic dermatitis, cystic fibrosis, chronic obstructivebronchitis and asthma(v) endometriosis, uterine fibroids, endometrial hyperplasia and benignprostate hyperplasia(vi) cardiac dysfunction(vii) inhibiting immunosuppressive conditions like HIV infections(viii) neuropathological disorders like Parkinson disease, Alzheimerdisease or polyglutamine related disorders(ix) pathological conditions amenable to treatment by potentiating ofendogenous gene expression as well as enhancing transgene expression ingene therapy.

Compounds according to the present invention may commercially applicablefor treatment, prevention or amelioration of the diseases of benign andmalignant behavior as described herein, such as, for example,(hyper)proliferative diseases and/or disorders responsive to inductionof apoptosis and/or disorders responsive to cell differentiation, e.g.benign or malignant neoplasia, particularly cancer, such as e.g. any ofthose cancer diseases described above.

In the context of their properties, functions and usabilities mentionedherein, the compounds according to the present invention are expected tobe distinguished by valuable and desirable effects related therewith,such as e.g. by low toxicity, superior bioavailability in general (suchas e.g. good enteral absorption), superior therapeutic window, absenceof significant side effects, and/or further beneficial effects relatedwith their therapeutic and pharmaceutical suitability.

Crystalline compounds according to this invention, e.g. crystallinesalts according to this invention, particularly when those compounds arein a specific crystal form (polymorph), are expected to have desirablephysicochemical properties that differ from those of any amorphous formand such properties may beneficially influence the chemical and solidstate stability, as well as the chemical and pharmaceutical processing,formulating and mechanical handling on a commercial scale. Thus, thosecrystalline compounds may be particularly suited for the manufacture ofcommercially viable and pharmaceutically acceptable drug compositions ordosage forms.

The present invention provides compounds according to this invention incrystalline form.

Also, the present invention provides compounds according to thisinvention, including their crystalline forms, isolated in purified orsubstantially pure form, such as e.g. greater than about 50%, moreprecisely about 60%, more precisely about 70%, more precisely about 80%,more precisely about 90%, more precisely bout 95%, more precisely about97%, more precisely about 99% wt purity as determined by art-knownmethods.

Also, the present invention provides crystalline compounds according tothis invention in substantially pure form, such as e.g. greater thanabout 50%, more precisely about 60%, more precisely about 70%, moreprecisely about 80%, more precisely about 90%, more precisely bout 95%,more precisely about 97%, more precisely about 99% wt purity asdetermined by art-known methods, e.g. by XRPD. In this context, thepresent invention provides crystalline compounds according to thisinvention, including specific crystalline polymorphs thereof,substantially devoid of amorphous materials, such as e.g. less thanabout 50%, more precisely 40%, more precisely 30%, more precisely 20%,more precisely 10%, more precisely 5%, more precisely 3%, more precisely1% wt are amorphous forms of the respective compounds as determined byart-known methods, e.g. by XRPD.

Also, the present invention provides specific crystalline polymorphs ofcompounds according to this invention in substantially pure form, suchas e.g. greater than about 60%, more precisely about 70%, more preciselyabout 80%, more precisely about 90%, more precisely bout 95%, moreprecisely about 97%, more precisely about 99% wt purity as determined byart-known methods, e.g. by XRPD.

Also, the present invention provides specific crystalline polymorphs ofcompounds according to this invention in substantially pure form, suchas e.g. less than about 40%, more precisely about 30%, more preciselyabout 20%, more precisely about 10%, more precisely bout 5%, moreprecisely about 3%, more precisely about 1% wt is not said polymorph asdetermined by art-known methods, e.g. by XRPD.

Accordingly, the present invention provides specific crystallinepolymorphs of compounds according to this invention substantially devoidof other crystalline forms.

Also, the present invention provides compounds according to thisinvention, including their crystalline forms, in a pharmaceuticallyacceptable form.

Also, the present invention provides compounds according to thisinvention, including their crystalline forms, in a pharmaceuticallyacceptable form capable of being milled or in a milled form.

Also, the present invention provides compounds according to thisinvention, including their crystalline forms, in solid pharmaceuticallyacceptable forms, particularly solid oral dosage forms, such as tabletsand capsules.

The present invention further includes a method for the treatment ofmammals, including humans, which are suffering from one of theabovementioned conditions, illnesses, disorders or diseases. The methodis characterized in that a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto this invention, which function by inhibiting histone deacetylases and-in general-by modulating protein acetylation, induce various cellulareffects, in particular induction or repression of gene expression,arresting cell proliferation, inducing cell differentiation and/orinducing apoptosis, is administered to the subject in need of suchtreatment.

The invention further includes a method for treating diseases and/ordisorders responsive or sensitive to the inhibition of histonedeacetylases, particularly those diseases mentioned above, such as e.g.cellular neoplasia or diseases different to cellular neoplasia asindicated above, in mammals, including humans, suffering therefromcomprising administering to said mammals in need thereof apharmacologically active and therapeutically effective and tolerableamount of one or more of the compounds according to the presentinvention.

The present invention further includes a therapeutic method useful tomodulate protein acetylation, gene expression, cell proliferation, celldifferentiation and/or apoptosis in vivo in diseases mentioned above, inparticular cancer, comprising administering to a subject in need of suchtherapy a pharmacologically active and therapeutically effective andtolerable amount of one or more of the compounds according to thisinvention, which function by inhibiting histone deacetylases.

The present invention further provides a method for regulatingendogenous or heterologous promotor activity by contacting a cell with acompound according to this invention.

The invention further includes a method for treating diseases,particularly those diseases mentioned above, in mammals, includinghumans, suffering therefrom comprising administering to said mammals inneed thereof a therapeutically effective and tolerable amount of one ormore of the compounds according to the present invention, optionally,simultaneously, sequentially or separately with one or more furthertherapeutic agents, such as e.g. those mentioned below.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionswhich are employed for the treatment and/or prophylaxis of the diseases,disorders, illnesses and/or conditions as mentioned herein.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionswhich are employed for the treatment and/or prophylaxis of diseasesand/or disorders responsive or sensitive to the inhibition of histonedeacetylases, particularly those diseases mentioned above, such as e.g.cellular neoplasia or diseases different to cellular neoplasia asindicated above.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionshaving histone deacetylase inhibitory activity.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionsfor inhibiting or treating cellular neoplasia, such as e.g. benign ormalignant neoplasia, e.g. cancer.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionswhich can be used for treating, preventing or ameliorating of diseasesresponsive to arresting aberrant cell growth, such as e.g.(hyper)proliferative diseases of benign or malignant behaviour, such ase.g. any of those diseases mentioned herein, particularly cancer, suchas e.g. any of those cancer diseases described herein above.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionswhich can be used for treating, preventing or ameliorating of disordersresponsive to induction of apoptosis, such as e.g. any of those diseasesmentioned herein, particularly cancer, such as e.g. any of those cancerdiseases described herein above.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionswhich can be used for treating, preventing or ameliorating of disordersresponsive to induction of differentiation, such as e.g. any of thosediseases mentioned herein, particularly cancer, such as e.g. any ofthose cancer diseases described herein above.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionswhich can be used for treating, preventing or ameliorating of benign ormalignant neoplasia, particularly cancer, such as e.g. any of thosecancer diseases described herein above.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionsfor the treatment of a disease different to a cellular neoplasia andsensitive to histone deacetylase inhibitor therapy, such as thenon-malignant diseases mentioned before.

The invention further relates to the use of the compounds according tothe present invention for the production of pharmaceutical compositionsfor inhibiting histone deacetylase activity in the treatment of diseasesresponsive to said inhibition or to the functional consequences thereof.

The invention further relates to a method for treating, preventing orameliorating the diseases, disorders, illnesses and/or conditionsmentioned herein in a mammal, in particular a human patient, comprisingadministering a pharmacologically active and therapeutically effectiveand tolerable amount of one or more compounds according to the presentinvention to said mammal in need thereof.

The invention further relates to the compounds according to thisinvention for use in the treatment and/or prophylaxis of diseases,especially the diseases mentioned.

The invention further relates to pharmaceutical compositions comprisingone or more of the compounds according to this invention and apharmaceutically acceptable carrier or diluent.

The present invention further relates to pharmaceutical compositionscomprising one or more of the compounds according to this invention andpharmaceutically acceptable auxiliaries and/or excipients.

The invention further relates to a combination comprising one or more ofthe compounds according to this invention and a pharmaceuticallyacceptable diluent, excipient and/or carrier, e.g. for treating,preventing or ameliorating (hyper)proliferative diseases of benign ormalignant behaviour and/or disorders responsive to induction ofapoptosis, such as, for example, benign or malignant neoplasia, e.g.cancer, such as e.g. any of those cancer diseases described hereinabove.

The invention further relates to pharmaceutical compositions accordingto this invention having histone deacetylases inhibitory activity.

The invention further relates to pharmaceutical compositions accordingto this invention having apoptosis inducing activity.

The invention further relates to pharmaceutical compositions accordingto this invention having anti-proliferative activity.

The invention further relates to pharmaceutical compositions accordingto this invention having cell differentiation inducing activity.

The invention further relates to the use of a pharmaceutical compositioncomprising one or more of the compounds according to this invention anda pharmaceutically acceptable carrier or diluent in the manufacture of apharmaceutical product, such as e.g. a commercial package, for use inthe treatment and/or prophylaxis of the diseases as Mentioned.

Additionally, the invention relates to an article of manufacture, whichcomprises packaging material and a pharmaceutical agent contained withinsaid packaging material, wherein the pharmaceutical agent istherapeutically effective for inhibiting the effects of histonedeacetylases, ameliorating the symptoms of an histone deacetylasemediated disorder, and wherein the packaging material comprises a labelor package insert which indicates that the pharmaceutical agent isuseful for preventing or treating histone deacetylase mediateddisorders, and wherein said pharmaceutical agent comprises one or morecompounds according to the invention. The packaging material, label andpackage insert otherwise parallel or resemble what is generally regardedas standard packaging material, labels and package inserts forpharmaceuticals having related utilities.

The pharmaceutical compositions according to this invention are preparedby processes which are known per se and familiar to the person skilledin the art. As pharmaceutical compositions, the compounds of theinvention (=active compounds) are either employed as such, or preferablyin combination with suitable pharmaceutical auxiliaries and/orexcipients, e.g. in the form of tablets, coated tablets, capsules,caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions,gels or solutions, the active compound content advantageously beingbetween 0.1 and 95% and where, by the appropriate choice of theauxiliaries and/or excipients, a pharmaceutical administration form(e.g. a delayed release form or an enteric form) exactly suited to theactive compound and/or to the desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries, vehicles,excipients, diluents, carriers or adjuvants which are suitable for thedesired pharmaceutical formulations, preparations or compositions onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used.

Depending upon the particular disease, to be treated or prevented,additional therapeutic active agents, which are normally administered totreat or prevent that disease, may optionally be coadministered with thecompounds according to the present invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease are known as appropriate for the disease beingtreated.

For example, the compounds according to this invention may be combinedwith standard therapeutic agents or radiation used for treatment of thediseases as mentioned before.

In one particular embodiment the compounds according to this inventionmay be combined with one or more art-known anti-cancer agents, such ase.g. with one or more art-known chemotherapeutic and/or target specificanti-cancer agents, e.g. with one or more of those described below,and/or radiation.

Examples of known chemotherapeutic anti-cancer agents frequently used incombination therapy include, but not are limited to (i)alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®),Ifosfamid (Holoxan®), Thiotepa (Thiotepa Lederle®), Melphalan(Alkeran®), or chloroethylnitrosourea (BCNU); (ii) platinum derivativeslike cis-platin (Platinex® BMS), oxaliplatin, satraplatin or carboplatin(Cabroplat® BMS); (iii) antimitotic agents/tubulin inhibitors such asvinca alkaloids (vincristine, vinblastine, vinorelbine), taxanes such asPaclitaxel (Taxol®), Docetaxel (Taxotere®) and analogs as well as newformulations and conjugates thereof, epothilones such as Epothilone B(Patupilone®), Azaepothilone (Ixabepilone®) or ZK-EPO, a fully syntheticepothilone B analog; (iv) topoisomerase inhibitors such asanthracyclines (exemplified by Doxorubicin /Adriblastin®),epipodophyllotoxines (exemplified by Etoposide/Etopophos®) andcamptothecin and camptothecin analogs (exemplified byIrinotecan/Camptosar® or Topotecan/Hycamtin®); (v) pyrimidineantagonists such as 5-fluorouracil (5-FU), Capecitabine (Xeloda®),Arabinosylcytosine /Cytarabin (Alexan®) or Gemcitabine (Gemzar®); (vi)purin antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanineor fludarabine (Fludara®) and finally (vii) folic acid antagonists suchas methotrexate (Farmitrexat®) or premetrexed (Alimta®).

Examples of target specific anti-cancer drug classes used inexperimental or standard cancer therapy include but are not limited to(i) kinase inhibitors such as e.g. Imatinib (Glivec®), ZD-1839/Gefitinib(Iressa®), Bay43-9006 (Sorafenib, Nexavar®), SU11248/Sunitinib (Sutent®)or OSI-774/Erlotinib (Tarceva®), Dasatinib (Sprycel®), Lapatinib(Tykerb®), or, see also below, Vatalanib, Vandetanib (Zactima®) orPazopanib; (ii) proteasome inhibitors such as PS-341/Bortezumib(Velcade®); (iii) heat shock protein 90 inhibitors like17-allylaminogeldanamycin (17-AAG); (iv) vascular targeting agents(VTAs) like combretastin A4 phosphate or AVE8062/AC7700 andanti-angiogenic drugs like the VEGF antibodies, such as Bevacizumab(Avastin®), or KDR tyrosine kinase inhibitors such as PTK787/ZK222584(Vatalanib) or Vandetanib (Zactima®) or Pazopanib; (v) monoclonalantibodies such as Trastuzumab (Herceptin®) or Rituximab(MabThera/Rituxan®) or Alemtuzumab (Campath®) or Tositumomab (Bexxar®)or C225/Cetuximab (Erbitux®) or Avastin (see above) or Panitumumab aswell as mutants and conjugates of monoclonal antibodies, e.g. Gemtuzumabozogamicin (Mylotarg®) or Ibritumomab tiuxetan (Zevalin®), and antibodyfragments; (vi) oligonucleotide based therapeutics likeG-3139/Oblimersen (Genasense®); (vii) Toll-like receptor /TLR 9 agonistslike Promune®, TLR 9 agonists like Imiquimod (Aldara®) or Isatoribineand analogues thereof, or TLR 7/8 agonists like Resiquimod as well asimmunostimulatory RNA as TLR 7/8 agonists; (viii) protease inhibitors(ix) hormonal therapeutics such as anti-estrogens (e.g. Tamoxifen orRaloxifen), anti-androgens (e.g. Flutamide or Casodex), LHRH analogs(e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors.

Other known target specific anti-cancer agents which can be used forcombination therapy include bleomycin, retinoids such as all-transretinoic acid (ATRA), DNA methyltransferase inhibitors such as the2-deoxycytidine derivative Decitabine (Docagen®) and 5-Azacytidine,alanosine, cytokines such as interleukin-2, interferons such asinterferon α2 or interferon-γ, death receptor agonists, such as TRAIL,DR4/5 agonistic antibodies, FasL and TNF-R agonists (e.g. TRAIL receptoragonists like mapatumumab or lexatumumab), and finally histonedeacetylase inhibitors different to the compounds according to thisinvention such as SAHA, PXD101, MS275, MGCD0103, Depsipeptide/FK228,NVP-LBH589, NVP-LAQ824, Valproic acid (VPA) and butyrates.

As exemplary anti-cancer agents for use in combination with thecompounds according to this invention in the cotherapies mentionedherein any of the following drugs may be mentioned, without beingrestricted thereto, 5 FU, actinomycin D, ABARELIX, ABCIXIMAB,ACLARUBICIN, ADAPALENE, ALEMTUZUMAB, ALTRETAMINE, AMINOGLUTETHIMIDE,AMIPRILOSE, AMRUBICIN, ANASTROZOLE, ANCITABINE, ARTEMISININ,AZATHIOPRINE, BASILIXIMAB, BENDAMUSTINE, BEVACIZUMAB, BEXXAR,BICALUTAMIDE, BLEOMYCIN, BORTEZOMIB, BROXURIDINE, BUSULFAN, CAMPATH,CAPECITABINE, CARBOPLATIN, CARBOQUONE, CARMUSTINE, CETRORELIX,CHLORAMBUCIL, CHLORMETHINE, CISPLATIN, CLADRIBINE, CLOMIFENE,CYCLOPHOSPHAMIDE, DACARBAZINE, DACLIZUMAB, DACTINOMYCIN, DASATINIB,DAUNORUBICIN, DECITABINE, DESLORELIN, DEXRAZOXANE, DOCETAXEL,DOXIFLURIDINE, DOXORUBICIN, DROLOXIFENE, DROSTANOLONE, EDELFOSINE,EFLORNITHINE, EMITEFUR, EPIRUBICIN, EPITIOSTANOL, EPTAPLATIN, ERBITUX,ERLOTINIB, ESTRAMUSTINE, ETOPOSIDE, EXEMESTANE, FADROZOLE, FINASTERIDE,FLOXURIDINE, FLUCYTOSINE, FLUDARABINE, FLUOROURACIL, FLUTAMIDE,FORMESTANE, FOSCARNET, FOSFESTROL, FOTEMUSTINE, FULVESTRANT, GEFITINIB,GENASENSE, GEMCITABINE, GLIVEC, GOSERELIN, GUSPERIMUS, HERCEPTIN,IDARUBICIN, IDOXURIDINE, IFOSFAMIDE, IMATINIB, IMPROSULFAN, INFLIXIMAB,IRINOTECAN, IXABEPILONE, LANREOTIDE, LAPATINIB, LETROZOLE, LEUPRORELIN,LOBAPLATIN, LOMUSTINE, LUPROLIDE, MELPHALAN, MERCAPTOPURINE,METHOTREXATE, METUREDEPA, MIBOPLATIN, MIFEPRISTONE, MILTEFOSINE,MIRIMOSTIM, MITOGUAZONE, MITOLACTOL, MITOMYCIN, MITOXANTRONE,MIZORIBINE, MOTEXAFIN, MYLOTARG, NARTOGRASTIM, NEBAZUMAB, NEDAPLATIN,NILUTAMIDE, NIMUSTINE, OCTREOTIDE, ORMELOXIFENE, OXALIPLATIN,PACLITAXEL, PALIVIZUMAB, PANITUMUMAB, PATUPILONE, PAZOPANIB,PEGASPARGASE, PEGFILGRASTIM, PEMETREXED, PENTETREOTIDE, PENTOSTATIN,PERFOSFAMIDE, PIPOSULFAN, PIRARUBICIN, PLICAMYCIN, PREDNIMUSTINE,PROCARBAZINE, PROPAGERMANIUM, PROSPIDIUM CHLORIDE, RALOXIFEN,RALTITREXED, RANIMUSTINE, RANPIRNASE, RASBURICASE, RAZOXANE, RITUXIMAB,RIFAMPICIN, RITROSULFAN, ROMURTIDE, RUBOXISTAURIN, SARGRAMOSTIM,SATRAPLATIN, SIROLIMUS, SOBUZOXANE, SORAFENIB, SPIROMUSTINE,STREPTOZOCIN, SUNITINIB, TAMOXIFEN, TASONERMIN, TEGAFUR, TEMOPORFIN,TEMOZOLOMIDE, TENIPOSIDE, TESTOLACTONE, THIOTEPA, THYMALFASIN,TIAMIPRINE, TOPOTECAN, TOREMIFENE, TRAIL, TRASTUZUMAB, TREOSULFAN,TRIAZIQUONE, TRIMETREXATE, TRIPTORELIN, TROFOSFAMIDE, UREDEPA,VALRUBICIN, VATALANIB, VANDETANIB, VERTEPORFIN, VINBLASTINE,VINCRISTINE, VINDESINE, VINORELBINE, VOROZOLE and ZEVALIN.

The anti-cancer agents mentioned herein above as combination partners ofthe compounds according to this invention are meant to includepharmaceutically acceptable derivatives thereof, such as e.g. theirpharmaceutically acceptable salts.

The person skilled in the art is aware on the base of his/her expertknowledge of the kind, total daily dosage(s) and administration form(s)of the additional therapeutic agent(s) coadministered. Said total dailydosage(s) can vary within a wide range.

In practicing the present invention and depending on the details,characteristics or purposes of their uses mentioned above, the compoundsaccording to the present invention may be administered in combinationtherapy separately, sequentially, simultaneously, concurrently orchronologically staggered (e.g. as combined unit dosage forms, asseparate unit dosage forms or a adjacent discrete unit dosage forms, asfixed or non-fixed combinations, as kit-of-parts or as admixtures) withone or more standard therapeutics, in particular art-knownchemotherapeutic and/or target specific anti-cancer agents, such as e.g.any of those mentioned above.

Thus, a further aspect of the present invention is a combination orpharmaceutical composition comprising a first active ingredient, whichis a compound according to this invention, a second active ingredient,which is an art-known standard therapeutic, in particular art-knownchemotherapeutic or target specific anti-cancer agent, such as one ofthose mentioned above, and optionally a pharmacologically acceptablecarrier, diluent and/or excipient for sequential, separate, simultaneousor chronologically staggered use in therapy in any order, e.g. to treat,prevent or ameliorate in a patient diseases responsive to HDAC inhibitortreatment, such as the diseases, disorders or illnesses mentioned, inparticular cancer.

In this context, the present invention further relates to a combinationcomprising a first active ingredient, which is at least one compoundaccording to this invention, and a second active ingredient, which is atleast one art-known standard therapeutic, for example an art-knownanti-cancer agent, such as e.g. one or more of those mentioned hereinabove, for separate, sequential, simultaneous, concurrent orchronologically staggered use in therapy, such as e.g. in therapy of anyof those diseases mentioned herein.

The term “combination” according to this invention may be present as afixed combination, a non-fixed combination or a kit-of-parts.

A “fixed combination” is defined as a combination wherein the said firstactive ingredient and the said second active ingredient are presenttogether in one unit dosage or in a single entity. One example of a“fixed combination” is a pharmaceutical composition wherein the saidfirst active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A “kit-of-parts” is defined as a combination wherein the said firstactive ingredient and the said second active ingredient are present inmore than one unit. One example of a “kit-of-parts” is a combinationwherein the said first active ingredient and the said second activeingredient are present separately. The components of the kit-of-partsmay be administered separately, sequentially, simultaneously,concurrently or chronologically staggered.

The first and second active ingredient of a combination or kit-of-partsaccording to this invention may be provided as separate formulations(i.e. independently of one another), which are subsequently broughttogether for simultaneous, sequential, separate or chronologicallystaggered use in combination therapy; or packaged and presented togetheras separate components of a combination pack for simultaneous,concurrent, sequential, separate or chronologically staggered use incombination therapy.

The type of pharmaceutical formulation of the first and second activeingredient of a combination or kit-of-parts according to this inventioncan be similar, i.e. both ingredients are formulated in separate tabletsor capsules, or can be different, i.e. suited for differentadministration forms, such as e.g. one active ingredient is formulatedas tablet or capsule and the other is formulated for e.g. intravenousadministration.

The amounts of the first and second active ingredients of thecombinations, compositions or kits according to this invention maytogether comprise a therapeutically effective amount for the treatment,prophylaxis or amelioration of a disease responsive or sensitive theinhibition of histone deacetylases, particularly one of those diseasesmentioned herein, e.g. benign or malignant neoplasia, particularlycancer, like any one of those cancer diseases mentioned herein.

A further aspect of the present invention is a combination comprising,in non-fixed form, one or more N-sulphonylpyrrole derivatives accordingto this invention or the salts thereof, and one or more art-knownstandard therapeutic, in particular art-known chemotherapeutic or targetspecific anti-cancer agents, such as those mentioned above, forsequential, separate, simultaneous or chronologically staggered use intherapy in any order, e.g. to treat, prevent or ameliorate in a patientdiseases responsive to HDAC inhibitor treatment, such as the diseases,disorders or illnesses mentioned, in particular cancer. Optionally saidcombination comprises instructions for its use in therapy.

A further aspect of the present invention is a combined preparation,such as e.g. a kit of parts, comprising a preparation of a first activeingredient, which is a compound according to this invention and apharmaceutically acceptable carrier or diluent; a preparation of asecond active ingredient, which is an art-known therapeutic agent, inparticular an anti-cancer agent, such as e.g. one of those mentionedabove, and a pharmaceutically acceptable carrier or diluent; andoptionally instructions for simultaneous, sequential, separate orchronologically staggered use in therapy, e.g. to treat benign andmalignant neoplasia or diseases different to cellular neoplasiaresponsive or sensitive to the inhibition of histone deacetylases.

A further aspect of the present invention is a kit of parts comprising adosage unit of a first active ingredient, which is a sulphonylpyrrolederivative mentioned in above or a salt thereof, a dosage unit of asecond active ingredient, which is an art-known standard therapeutic, inparticular an anti-cancer agent such as e.g. one of those mentionedabove, and optionally instructions for simultaneous, sequential orseparate use in therapy, e.g. to treat disorders responsive or sensitiveto the inhibition of histone deacetylases, such as, for example, benignor malignant neoplasia, e.g. cancer.

A further aspect of the present invention is a pharmaceutical productcomprising one or more compounds according to this invention, or one ormore pharmaceutical compositions comprising said compounds; and one ormore art-known therapeutic agents, in particular art-known anti-canceragents, or one or more pharmaceutical compositions comprising saidtherapeutic agents, such as e.g. those mentioned above, forsimultaneous, sequential or separate use in therapy, e.g. to treatdiseases as mentioned before, in particular cancer. Optionally thispharmaceutical product comprises instructions for use in said therapy.

In this connection, the present invention further relates tocombinations, compositions, formulations, preparations or kits accordingto the present invention having histone deacetylases inhibitoryactivity.

A further aspect of the present invention is a pharmaceuticalcomposition as unitary dosage form comprising, in admixture, a firstactive ingredient, which is a N-sulphonylpyrrole derivative according tothis invention or a salt thereof, a second active ingredient, which isan art-known standard therapeutic, in particular art-knownchemotherapeutic or target specific anti-cancer agent, such as one ofthose mentioned above, and optionally a pharmacologically acceptablecarrier, diluent or excipient.

The present invention further relates to a pharmaceutical compositioncomprising a first active ingredient, which is at least one compoundaccording to this invention, and a second active ingredient, which is atleast one art-known anti-cancer agent, such as e.g. one or more of thosementioned herein above, and, optionally,

a pharmaceutically acceptable carrier or diluent, for separate,sequential, simultaneous, concurrent or chronologically staggered use intherapy, such as e.g. in therapy of diseases responsive or sensitive tothe inhibition of histone deacetylases, particularly(hyper)proliferative diseases and/or disorders responsive to inductionof apoptosis, such as e.g. any of those diseases mentioned herein, likebenign or malignant neoplasia, especially cancer, particularly any ofthose cancer diseases described above.

The present invention further relates to a combination productcomprising

a.) at least one compound according to this invention formulated with apharmaceutically acceptable carrier or diluent, andb.) at least one art-known anti-cancer agent, such as e.g. one or moreof those mentioned herein above, formulated with a pharmaceuticallyacceptable carrier or diluent.

The present invention further relates to a kit-of-parts comprising apreparation of a first active ingredient, which is a compound accordingto this invention, and a pharmaceutically acceptable carrier or diluent;a preparation of a second active ingredient, which is an art-knownanti-cancer agent, such as one of those mentioned above, and apharmaceutically acceptable carrier or diluent; for simultaneous,concurrent, sequential, separate or chronologically staggered use intherapy. Optionally, said kit comprises instructions for its use intherapy, e.g. to treat diseases responsive or sensitive to theinhibition of histone deacetylases, such as e.g. cellular neoplasia ordiseases different to cellular neoplasia as indicated above,particularly cancer, such as e.g. any of those cancer diseases describedabove.

The present invention further relates to a combined preparationcomprising at least one compound according to this invention and atleast one art-known anti-cancer agent for simultaneous, concurrent,sequential or separate administration.

In this connection, the present invention further relates tocombinations, compositions, formulations, preparations or kits accordingto the present invention having histone deacetylases inhibitoryactivity.

Also in this connection, the present invention further relates tocombinations, compositions, formulations, preparation or kits accordingto the present invention having anti-(hyper)proliferative and/orapoptosis inducing activity.

In addition, the present invention further relates to the use of acomposition, combination, formulation, preparation or kit according tothis invention in the manufacture of a pharmaceutical product, such ase.g. a commercial package or a medicament, for treating, preventing, orameliorating diseases responsive or sensitive to the inhibition ofhistone deacetylases, particularly those diseases mentioned herein, suchas e.g. benign or malignant neoplasia, particularly cancer.

The present invention further relates to a commercial package comprisingone or more compounds of the present invention together withinstructions for simultaneous, sequential or separate use with one ormore chemotherapeutic and/or target specific anti-cancer agents, such ase.g. any of those mentioned herein.

The present invention further relates to a commercial package consistingessentially of one or more compounds of the present invention as soleactive ingredient together with instructions for simultaneous,sequential or separate use with one or more chemotherapeutic and/ortarget specific anti-cancer agents, such as e.g. any of those mentionedherein.

The present invention further relates to a commercial package comprisingone or more chemotherapeutic and/or target specific anti-cancer agents,such as e.g. any of those mentioned herein, together with instructionsfor simultaneous, sequential or separate use with one or more compoundsaccording to the present invention.

Furthermore, also an aspect of the present invention is a method fortreating diseases and/or disorders responsive or sensitive to theinhibition of histone deacetylases, e.g. (hyper)proliferative diseasesand/or disorders responsive to induction of apoptosis, such as e.g.cancer, in combination therapy in a patient comprising administering apharmacologically active and therapeutically effective and tolerableamount of a pharmaceutical combination, composition, formulation,preparation or kit as described above to said patient in need thereof.

A further aspect of the present invention is a method for treatingcotherapeutically diseases responsive or sensitive to inhibiting histonedeacetylases, such as e.g. those diseases as mentioned before,particularly cancer, in a patient in need of such treatment comprisingadministering separately, sequentially, simultaneously, concurrently,fixed or non-fixed a pharmacologically active and therapeuticallyeffective and tolerable amount of one or more of the compounds accordingto the present invention and a pharmacologically active andtherapeutically effective and tolerable amount of one or more art-knowntherapeutic agents, in particular anti-cancer agents, such as thosementioned above, to said patient.

In further addition, the present invention relates to a method fortreating, preventing or ameliorating (hyper)proliferative diseasesand/or disorders responsive to induction of apoptosis, such as e.g.benign or malignant neoplasia, e.g. cancer, particularly any of thosecancer diseases mentioned herein, in a patient comprising administeringseparately, simultaneously, concurrently, sequentially orchronologically staggered to said patient in need thereof an amount of afirst active compound, which is a compound according to the presentinvention, and an amount of at least one second active compound, said atleast one second active compound being a standard therapeutic agent,particularly at least one art-known anti-cancer agent, such as e.g. oneor more of those chemotherapeutic and target-specific anti-cancer agentsmentioned herein, wherein the amounts of the first active compound andsaid second active compound result in a therapeutic effect.

In yet further addition, the present invention relates to a method fortreating, preventing or ameliorating (hyper)proliferative diseasesand/or disorders responsive to induction of apoptosis, such as e.g.benign or malignant neoplasia, e.g. cancer, particularly any of thosecancer diseases mentioned herein, in a patient comprising administeringa combination according to the present invention.

The pharmaceutical compositions, combinations, preparations,formulations, kits, products or packages mentioned above may alsoinclude more than one of the compounds according to this inventionand/or more than one of the art-known standard therapeutics, inparticular anti-cancer agents as mentioned.

In addition, compounds according to the present invention can be used inthe pre- or post-surgical treatment of cancer.

In further addition, compounds according to the present invention can beused in combination with radiation therapy, in particular insensitization of cancer patients towards standard radiation therapy.

The administration of the compounds according to this invention, thecombinations and pharmaceutical compositions according to the inventionmay be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdermal and rectal delivery. Oral and intravenous deliveryare preferred.

For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosepharmaceutical compositions which are suitable for topical application.For the production of the pharmaceutical compositions, the compounds ofthe invention (=active compounds) are preferably mixed with suitablepharmaceutical auxiliaries and further processed to give suitablepharmaceutical formulations. Suitable pharmaceutical formulations are,for example, powders, emulsions, suspensions, sprays, oils, ointments,fatty ointments, creams, pastes, gels or solutions.

The pharmaceutical compositions according to the invention are preparedby processes known per se. The dosage of the compounds according to theinvention (=active compounds) is carried out in the order of magnitudecustomary for histone deacetylases inhibitors. Topical application forms(such as ointments) for the treatment of dermatoses thus contain theactive compounds in a concentration of, for example, 0.1-99%. Thecustomary dose in the case of systemic therapy (p.o.) may be between0.03 and 60 mg/kg per day, (i. v.) may be between 0.03 and 60 mg/kg/h.In another embodiment, the customary dose in the case of systemictherapy (p.o.) is between 0.3 and 30 mg/kg per day, (i. v.) is between0.3 and 30 mg/kg/h.

The choice of the optimal dosage regime and duration of medication,particularly the optimal dose and manner of administration of the activecompounds necessary in each case can be determined by a person skilledin the art on the basis of his/her expert knowledge.

Biological Investigations

Isolation of HDAC Activity from Hela Cell Nuclei:

HDAC activity was isolated from nuclear HeLa extracts according to amethod original described by Dignam et al. (Nucl. Acids Res. 11, pp1475, 1983). Briefly, nuclei isolated from HeLa cells (CIL SA, Seneffe,Belgium) were resuspended in buffer C (20 mM Hepes pH 7.9, 25% v:vglycerol, 0.42M NaCl, 1.5 mM MgCl₂, 0.2 mM EDTA, 0.5 mM PefaBloc and 0.5mM DTT) and stirred for 30 min on ice. After centrifugation, thesupernatant was dialysed against buffer D (40 mM Tris HCl pH 7.4, 100 mMKCl, 0.2 mM EDTA, 0.5 mM DTT and 25% v:v glycerol) for 5 h at 4° C.After dialysis and centrifugation, the supernatant was stored inaliquots at −80° C. and used for Western blot analysis as well as theenzymatic assay as described in the following.

Isolation of rHDAC1

Human HDAC1 fused with the flag epitope is stably expressed in Hek293cells. After mass cultivation in DMEM with supplements and 2% fetal calfserum, cells are lysed and flag-HDAC1 purified by M2-agarose affinitychromatography as described (Sigma Art. No. A-2220). Fractions from thepurification are analysed by Western blot as well as for enzymaticactivity as described below.

Fluorimetric HDAC Activity Assay:

The HDAC enzyme activity assay was done as described by Wegener et al.(Chem. & Biol. 10, 61-68, 2003). Briefly 40 μl of a 1:100 dilution (=0.4μl) nuclear HeLa extract (mixture of class I and 11 HDACs), 29 μl enzymebuffer (15 mM Tris HCl pH 8.1, 0.25 mM EDTA, 250 mM NaCl, 10% v:vglycerol) and 1 μl test compound were added to a well of a 96 wellmicrotiter plate and reaction started by addition of 30 μl substrate(Ac—NH-GGK(Ac)-AMC; final concentration 25 μM and final volume 100 μl).After incubation for 90 min at 30° C., reaction was terminated by theaddition of 25111 stop solution (50 mM Tris HCl pH 8, 100 mM NaCl, 0.5mg/ml trypsine and 2 μM TSA). After incubation at room temperature forfurther 40 min, fluorescence was measured using a Wallac Victor 1420multilabel counter (Ex 355 nm, Em 460 nm) for quantification of AMC(7-amino-4-methylcoumarin) generated by trypsine cleavage of thedeacetylated peptide. For the calculation of IC₅₀ values thefluorescence in wells without test compound (1% DMSO, negative controlwas set as 100% enzymatic activity and the fluorescence in wells with 2μM TSA (positive control) were set at 0% enzymatic activity. Thecorresponding IC₅₀ values of the compounds for HDAC inhibitory activitywere determined from the concentration-effect curves by means ofnon-linear regression.

The HDAC inhibitory activity expressed by IC₅₀ values for selectedcompounds according to the present invention is shown in the followingtable 1, in which the numbers of the compounds correspond to the numbersof the examples.

TABLE 1 HDAC inhibitory activity (HDAC activity isolated from HeLanuclear extract) Compound IC₅₀ (μM) 1 The IC₅₀ values of these 2 listedcompounds are in 3 the range from 0.0036 to 2.74 4 7 8 9 to 28 The IC₅₀values of these listed compounds are in the range from 0.002 to 40

The HDAC1 enzymatic assay is done with slight modifications withrecombinant flag-HDAC1 protein isolated from HEK293 cell lysates. About14 ng/well flag-HDAC1 were incubated with 6 μM Ac—NH-GGK(Ac)-AMCsubstrate for 3 h at 30° C. Termination of the reaction and all furthersteps are done as described for HeLa cell nuclear extracts as a sourcefor HDAC enzymatic activity.

Recombinant human HDAC1 expressed in Hek293 cells is inhibited byExamples 3, 4, 5, 7, 8 to 11, 24, 25, 27 and 28 with an IC₅₀≧0.95 nM.

Cellular Histone H3 Hyperacetylation Assay:

To assess the cellular efficacy of a histone deacetylase inhibitor invitro, an assay was set up in black clear-bottom 96-well plates andoptimized for use on the Cellomics “ArrayScan II” platform for aquantitative calculation of histone acetylation. The protocol uses apolyclonal rabbit antibody, specifically binding to acetylated lysine 23or, alternatively, acetylated lysine 9+14 of human histone H3 on fixedcells with an Alexa Fluor 488 labeled goat anti rabbit-IgG used forcounterstaining (modified from Braunger et al. AACR annual conference2003, Abstract 4556). 5×10³ HeLa cervical carcinoma cells/well (ATCCCCL-2) in 200 μl Dulbecco's modified Eagle's medium (DMEM) containing10% fetal calf serum are seeded at day 1 in Packard view plates andincubated for 24 h under standard cell culture conditions. On day 2, 1μl test compound (200× final concentration) is added and incubationcontinued for further 24 h. On day 3, the culture medium is discardedand attached cells fixed for 15 min at room temperature by addition of100 μl fixation buffer (3.7% v:v formaldehyde in phosphate bufferedsaline/PBS). After discarding the fixation buffer and one wash withblocking solution (1% BSA, 0.3% Tween 20 in PBS), cells arepermeabilized at room temperature by addition of 100 μl /wellpermeabilization buffer (30.8 mM NaCl, 0.54 mM Na₂HPO₄, 0.31 mM KH₂PO₄,0.1% v:v Triton X-10.0) for 15 min at room temperature. After discardingthe permeabilization buffer and washing twice with 100 μl/well blockingsolution at room temperature, the 1^(st) antibody (anti-K23 histone H3antibody, Cell Signaling No. 9674 or, alternatively, anti-K9+14 histoneH3 antibody, Calbiochem No. 382158) in blocking solution (50 μl/well) isadded. After incubation for 1 h at room temperature, the wells arewashed twice at room temperature with 100 μl/well blocking solutionbefore addition of the 2^(nd) antibody (goat-anti-rabbit Alexa Fluor488; MoBiTec No. A-11008) in blocking solution (50 μl/well). Afterfurther incubation for 1 h at room temperature, wells are washed twicewith 100 μl/well blocking solution at room temperature. Finally, 100μl/well PBS are added and image analysis performed on the Cellomics“ArrayScan II” platform. For EC₅₀ determination, the percentage ofpositive cells showing nuclear fluorescence is determined and EC₅₀calculation done from concentration-effect curves by means of non-linearregression. For calibration, a positive (reference HDAC inhibitors likeSAHA or NVP LBH-589) and a negative control were included.

The histone hyperacetylating cellular potency expressed by EC₅₀ valuesfor selected compounds according to the present invention is shown inthe following table 2, in which the numbers of the compounds correspondto the numbers of the examples.

TABLE 2 Induction of histone H3 hyperacetylation in HeLa cervicalcarcinoma cells Compound EC₅₀ (μM) 1 The EC₅₀ values of these 2 listedcompounds are in 3 the range from 2.15 to 51.3 4 7 8 9, 10 and 27 3, 9,10 and 24 The EC₅₀ values of these listed compounds are in the rangefrom 0.08 to 16

Cellular Cytotoxicity Assay:

The anti-proliferative activity of the histone deacetylase inhibitorycompounds as described herein, was evaluated using the following celllines: HeLa and HeLa—KB (cervical carcinoma), H460 (non small cell lungcancer), A549 (non-small cell lung cancer), MCF7 (breast carcinoma),MCF10A (normal, non tumorigenic breast epithelial), MDA-MB468 (breastcarcinoma), MDA-MB435 (breast carcinoma), MDA-MB231 (breast carcinoma),SKBR-3 (breast carcinoma), SKOV-3 (ovarial carcinoma), A-2780 (ovarialcarcinoma), RKO (colon carcinoma), HCT-15 (colon carcinoma), HCT-116(colon carcinoma), PC3 (prostate carcinoma), BPH1 (benign prostatehyperplasia), AsPC1 (pancreatic carcinoma), Cal27 (tongue carcinoma),A-431 (vulva carcinoma), HeclA (endometrial carcinoma), Saos-2(osteosarcoma), U87MG (glioblastoma), WM266-4 (melanoma), K562 (chronicmyeloid carcinoma), EOL1 (acute hypereosinophilic myeloid leukemia),CCRF-CEM and CCRF-CEM VCR1000 (acute lymphoblastic leukemia sensitiveand resistant towards Vincristine). For quantification of cellularproliferation/living cells the Alamar Blue (Resazurin) cell viabilityassay was applied (O'Brien et al. Eur J Biochem 267, 5421-5426, 2000).In this assay Resazurin is reduced to the fluorescent resorufin bycellular dehydrogenase activity, correlating with viable, proliferatingcells. The examples were dissolved as 20 mM solutions indimethylsulfoxide (DMSO) and subsequently diluted in semi-logarithmicsteps. Cell lines were seeded at respective density into 96 well flatbottom plates in a volume of 200 μl per well. 24 hours after seeding 1μl each of the compound dilutions were added into each well of the 96well plate. Each compound dilution was tested as quadruplicates. Wellscontaining untreated control cells were filled with 200 μl DMEM mediumcontaining 0.5% v:v DMSO. The cells were then incubated with thesubstances for 72 hours at 37° C. in a humidified atmosphere containing5% carbon dioxide. To determine the viability of the cells, 20 μl of anResazurin solution (Sigma; 90 mg/l) were added. After 4 hours incubationat 37° C. the fluorescence was measured at an extinction of 544 nm andan emission of 590 nm. For the calculation of the cell viability theemission value from untreated cells was set as 100% viability and theemission rates of treated cells were set in relation to the values ofuntreated cells. Viabilities were expressed as % values. Thecorresponding IC₅₀ values of the compounds for cytotoxic activity aredetermined from the concentration-effect curves by means of non-linearregression.

For combination experiments, examples 3, 9, 10 and 24 around the IC₅₀concentration (as determined from the Alamar Blue assay) were tested incombination with respective anti-cancer agents Taxol, Docetaxel, 5-Fu,Irinotecan, Doxorubicin, Carboplatin, Cisplatin, Gemcitabine,Mafosfamide and Trail at variable concentrations. The concentration ofexamples used in these combination experiments were as follows: 0.4 μM(ex. 3), 2.5 μM (ex. 9), 2.3 μM (ex. 10) and 0.25 μM (ex. 24). A549non-small cell lung cancer, MDA-MB468 breast cancer and HCT-166colorectal cancer cell lines were pretreated with the examples for 4 hbefore adding the chemotherapeutic agents or Trail and furtherincubation for 72 h total. The IC₅₀ values of these combinations weredetermined from concentration-effect curves and compared to IC₅₀ valuesof cell treated with the anti-cancer agent only.

For determination of cell-cycle dependent cytotoxicity, the RKO exop21cell system was applied (Schmidt et al. Oncogene 19: 2423-2429, 2000).Briefly, RKO cells with/without p21^(waf1) expression (2×10⁴ cells/wellinduced, 6×10³ cells/well not induced) were treated with the examplesfor 72 h and metabolic activity quantified as described before. Theexpression of p21^(waf1) was induced by treatment with Pronasterone A,causing a complete proliferation arrest of RKO cells in the G1 and G2phases of the cell division cycle.

The anti-proliferative/cytotoxic potency expressed by IC₅₀ values forselected compounds according to the present invention is shown in thefollowing table 3, in which the numbers of the compounds correspond tothe numbers of the examples.

TABLE 3 Cytotoxicity in HeLa cervical carcinoma cells Compound IC₅₀ (μM)1 The IC₅₀ values of these 2 listed compounds are in 3 the range from0.8 to 21.6 4 7 8 9 to 28 The IC₅₀ values of these listed compounds arein the range from 0.07 to 5

The anti-proliferative activity of examples 3, 9, 10 and 24 is evaluatedby using a broad selection of non-malignant cell lines and fullytransformed malignant cancer cell lines. Mean IC₅₀ values are 0.85 μMfor ex. 3, 3.7 μM for ex. 9, 4.6 μM for ex. 10, and 0.57 μM for ex. 24.

Each of the examples 3, 9, 10 and 24 is combined at about its IC₅₀concentration with an anti-cancer agent selected from the groupconsisting of established chemotherapeutic and target-specificanti-cancer agents, such as, in one embodiment, with an antimitoticagent/tubulin inhibitor such as e.g a taxane like Taxol and Docetaxel,in a further embodiment, with a pyrimidine antagonist such as e.g. 5-FUand Gemcitabine, in a further embodiment, with a topoisomerase 1 or 2inhibitor such as e.g. camptothecin or a camptothecin analog (likeIrinotecan) or an anthracycline (like Doxorubicin), in a furtherembodiment, with an alkylating/carbamylating agent such as e.g.Mafosfamide, in a further embodiment, with a platinum derivative such ase.g. Carboplatin and Cisplatin) or, in a further embodiment, with adeath receptor agonist like the death receptor DR4/5 ligand Trail, usingthe mammary carcinoma model MDA-MB468, the colorectal carcinoma modelHCT116 and the non-small cell lung cancer model A549. For allchemotherapeutic agents mentioned above additive effects are noted (nosignificant effect of the combination on the IC₅₀ of thechemotherapeutic agent), whereas synergism is highly likely with Trailin the A549 cell line model.

By using proliferating and arrested RKO colon carcinoma cells withconditional p21^(waf1) expression as described above the proliferationindependent mode of action of examples 3, 9, 10 and 24 is shown (seetable 4). Dormant, non-proliferating as well as proliferating tumorcells are hit by the examples as described herein.

TABLE 4 Cell cycle independent cytotoxicity RKO arrested RKOproliferating (p21^(waf1) expressed) Compound IC₅₀ (μM) IC₅₀ (μM) 3, 9,10 and 24 The IC₅₀ values of these The IC₅₀ values of these listedcompounds are in listed compounds are in the the range from 0.15 to 5.1range from 0.45 to 15

Breast Cancer Cell Differentiation Assay

For quantification of MDA-MB468 breast cancer cell differentiation(described by Munster et al. Canc. Res. 61(23), pp 8492, 2001), 1×E6cells were seeded in 10 cm cell culture dishes and, after cultivationfor 24 h, treated with HDI for further 24 h. Finally, cells werecollected by trypsination, washed twice with PBS and resuspended in 1 mlof staining solution (51 g/ml Nile Red in PBS). After incubation for atleast 5 min at room temperature, cells were analysed by flow cytometryon a FACS Calibur device (Ex 488 nm, Em. at 530 nm/FL-1 and >630nm/FL-3). From respective histograms the percentage of cells withfluorescence at 650 nm (phospholipids) and 530 nm+650 nm (phospho- andneutral lipids) were calculated. For microscopic analysis, MDA-MB468cells were cultivated on two-well chamber slides, treated with testcompound for 24 h, fixed with 1.5 vol % glutaraldehyde/PBS and finallytreated with staining solution. After washing with PBS, cells wereanalysed by fluorescence microscopy.

MDA-MB468 cells are treated with examples 3, 9, 10 and 24 at therespective IC₅₀ and 2×IC₅₀ concentrations (as determined in cytotoxicityassays) for 24 h before analysis of phospholipid/neutral lipid contentby Nile Red staining and flow cytometry. The percentage ofdifferentiated cells with neutral and phospholipids as well asundifferentiated cells with phospholipids only are summarized in thetable 5.

TABLE 5 Induction of MDA-MB468 breast cancer cell differentiationNeutral & Concentration phospholipids Phospholipids Compound (μM) (%)(%) control 4.5 92.6 10 2 55.5 41.6 5 70.2 25.2 9 3 71.2 25.3 6 64.627.9 3 0.6 34.6 62.6 1.2 51.2 45.7 24 0.8 67.3 27.9 1.6 63.6 30.7

Apoptosis Induction

The induction of apoptosis was measured by using the cell deathdetection ELISA (Art. No. 1774425, Roche Biochemicals, Mannheim,Germany). A549 NSCLC cells were seeded into 96 well flat bottom platesat a density of 3×10 E3 cells/well in a total volume of 200 μl/well. 24hours after seeding, 1 μl each of the compound dilutions in DMEM wereadded in a total volume of 200 μl into each well. Each compound dilutionwas tested at least as triplicates. Wells containing untreated controlcells were filled with 200 μl DMEM containing 0.5 vol % DMSO. The cellswere incubated with test compound for 48 hours at 37° C. in a humidifiedatmosphere containing 5% carbon dioxide. As a positive control for theinduction of apoptosis, cells were treated with 50 μM Cisplatin (GryPharmaceuticals, Kirchzarten, Germany). Medium was then removed and thecells lysed in 200 μl lysis buffer. After centrifugation as described bythe manufacturer, 10 μl of cell lysate was processed as described in theprotocol. The degree of apoptosis was calculated as follows: Theabsorbance at 405 nm obtained with lysates from cells treated with 50 μMcisplatin is set as 100 cpu (cisplatin units), while an absorbance at405 nm of 0.0 is set as 0.0 cpu. The degree of apoptosis is expressed ascpu in relation to the value of 100 cpu reached with the lysatesobtained from cells treated with 50 μM cisplatin.

Representative apoptosis inducing potency values (expressed by cpuvalues) for compounds according to the present invention follows fromthe following table 6, in which the numbers of the compounds correspondto the numbers of the examples.

TABLE 6 Apoptosis induction Compound cpu @ 10 μM 3, 9, 10 and 24 The cpuvalues of these listed compounds are in the range from 248 to 380

1. A salt of a compound selected from the group consisting of(E)-N-hydroxy-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-amino)-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl)-acrylamide,(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide,and(E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamidewith hydrochloric acid, or a hydrate thereof or a crystalline form ofthis salt or hydrate.
 2. A salt of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidewith hydrochloric acid, or a hydrate thereof.
 3. The compound accordingto claim 1 being in crystalline form and having from about 0.1 to about1.9 equivalent hydrochloric acid with respect to the free base of saidcompound.
 4. A crystalline hydrochloride salt of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide,a hydrate or a polymorph thereof.
 5. A form A polymorph according toclaim 4 having a X-ray diffraction pattern, which comprises peaks atabout 5.8, 11.5, 15.0, 17.1, 17.4, 17.5, 18.2, 19.9, 20.1, 20.6, 21.3,21.5, 23.2, 24.1, 25.0, 25.4, 25.8, 26.9, 27.5, 28.5, 29.1, 30.1, 30.2,30.8 and 32.3 in 20; when the pattern is obtained using Cu Kα radiation.6. A form B polymorph according to claim 4 having a X-ray diffractionpattern, which comprises peaks at about 10.1, 17.0, 17.7, 17.9, 20.3,20.8, 21.1, 22.7, 23.1, 24.1, 26.2, 26.8, 27.9, 28.9 and 34.5 in 20;when the pattern is obtained using Cu Kα radiation.
 7. A salt of(E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamidewith hydrochloric acid, or a hydrate thereof.
 8. The compound accordingto claim 1 having from about 0.8 to about 1.2 equivalent hydrochloridewith respect to the free base of said compound.
 9. The compoundaccording to claim 1 having about one equivalent hydrochloride withrespect to the free base of said compound.
 10. The compound according toclaim 1 being in substantially pure form.
 11. The compound according toclaim 1 being substantially devoid of amorphous forms thereof.
 12. Thecompound according to claim 1 in solid dosage form.
 13. The compoundaccording to claim 1 in a pharmaceutically acceptable form.
 14. Aprocess for preparing a compound according to claim 4 comprising thestep of crystallization or recrystallization of any form or mixtures ofany forms of(E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamidewith hydrochloric acid in a solution comprising organic solvent ormixture of organic solvents, or mixtures thereof with water, or water.15. (canceled)
 16. A pharmaceutical composition comprising a compoundaccording to claim 1 together with a pharmaceutically acceptablediluent, excipient or carrier.
 17. (canceled)
 18. A method for treating,preventing or ameliorating hyperproliferative diseases of benign ormalignant behaviour and/or disorders responsive to induction ofapoptosis in a patient comprising administering to said patient atherapeutically effective and tolerable amount of a compound accordingto claim
 1. 19. A method for treating diseases responsive or sensitiveto inhibition of histone deacetylase activity in a patient comprisingadministering to said patient a therapeutically effective amount of acompound according to claim
 1. 20. A combination comprising a firstactive ingredient, which is at least one compound according to claim 1,and a second active ingredient, which is at least one anti-cancer agentselected from the group consisting of chemotherapeutic anti-canceragents and target-specific anti-cancer agents, for separate, sequential,simultaneous, concurrent or chronologically staggered use in therapy.21. A method for treating, preventing or ameliorating hyperproliferativediseases and/or disorders responsive to induction of apoptosis in apatient comprising administering separately, simultaneously,concurrently, sequentially or chronologically staggered to said patientin need thereof an amount of a first active compound, which is acompound according to claim 1, and an amount of at least one secondactive compound, said second active compound being an anti-cancer agentselected from the group consisting of chemotherapeutic anti-canceragents and target-specific anti-cancer agents, wherein the amounts ofthe first active compound and said second active compound result in atherapeutic effect.
 22. The combination according to claim 20, in whichsaid chemotherapeutic anti-cancer agents are selected from the groupconsisting of (i) alkylating/carbamylating agents; (ii) platinumderivatives; (iii) antimitotic agents/tubulin inhibitors; (iv)topoisomerase inhibitors; (v) pyrimidine antagonists; (vi) purinantagonists; (vii) folic acid antagonists.
 23. The combination accordingto claim 20, in which said target-specific anti-cancer agents areselected from (i) kinase inhibitors; (ii) proteasome inhibitors; (iii)histone deacetylase inhibitors; (iv) heat shock protein 90 inhibitors;(v) vascular targeting agents (VAT), anti-angiogenic drugs and KDRtyrosine kinase inhibitors; (vi) monoclonal antibodies, mutants andconjugates of monoclonal antibodies and antibody fragments; (vii)oligonucleotide based therapeutics; (viii) Toll-like receptor/TLR 9agonists, TLR 7 agonists, and TLR 7/8 agonists; (ix) proteaseinhibitors; (x) hormonal therapeutics; (xi) anti-androgens; (xii) LHRHanalogs; (xiii) aromatase inhibitors; (xiv) bleomycin; (xv) retinoids;(xvi) DNA methyltransferase inhibitors; (xvii) alanosine; (xviii)cytokines; (xix) interferons; and (xx) death receptor agonists.
 24. Thecombination according to claim 20, in which said target-specificanti-cancer agents are selected from the group consisting of deathreceptor agonists DR4/5 agonistic antibodies, and FasL and TNF-Ragonists.
 25. The method according to any claim 21, in which said canceris selected from the group consisting of cancer of the breast, bladder,bone, brain, central and peripheral nervous system, colon, endocrineglands, esophagus, endometrium, germ cells, head and neck, kidney,liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, ovary,pancreas, prostate, rectum, renal, small intestine, soft tissue, testis,stomach, skin, ureter, vagina and vulva; inherited cancers,retinoblastoma and Wilms tumor; leukemia, lymphoma, non-Hodgkinsdisease, chronic and acute myeloid leukaemia, acute lymphoblasticleukemia, Hodgkins disease, multiple myeloma and T-cell lymphoma; andmyelodysplastic syndrome, plasma cell neoplasia, paraneoplasticsyndromes, cancers of unknown primary site and AIDS relatedmalignancies.